WO2019127903A1 - 一种阿维巴坦的简便制备方法 - Google Patents
一种阿维巴坦的简便制备方法 Download PDFInfo
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- WO2019127903A1 WO2019127903A1 PCT/CN2018/078073 CN2018078073W WO2019127903A1 WO 2019127903 A1 WO2019127903 A1 WO 2019127903A1 CN 2018078073 W CN2018078073 W CN 2018078073W WO 2019127903 A1 WO2019127903 A1 WO 2019127903A1
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- 0 [*+]S(ON([C@]1CC[C@](C(N)=O)N2C1)C2=O)(=O)=O Chemical compound [*+]S(ON([C@]1CC[C@](C(N)=O)N2C1)C2=O)(=O)=O 0.000 description 9
- HYTSWLKLRKLRHK-NEPJUHHUSA-N NC([C@H](CC[C@H](C1)N2OCc3ccccc3)N1C2=O)=O Chemical compound NC([C@H](CC[C@H](C1)N2OCc3ccccc3)N1C2=O)=O HYTSWLKLRKLRHK-NEPJUHHUSA-N 0.000 description 1
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/08—Bridged systems
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- 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
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Definitions
- the invention relates to a simple preparation method of avivatan, belonging to the field of pharmaceutical biochemistry.
- Avidabatan (I) is a non- ⁇ -lactam inhibitor of diazabicyclooctyl ketone compound, and abibatan inhibits type A (including ESBL and KPC) and type C ⁇ -lactamase.
- Wabatan has a broad-spectrum antibacterial activity when used in combination with various cephalosporin and carbapenem antibiotics, especially for Escherichia coli and Klebsiella pneumoniae containing extended-spectrum ⁇ -lactamase, and contains excess AmpC enzyme. The activity of Escherichia coli and Escherichia coli containing both AmpC and extended-spectrum ⁇ -lactamase was remarkable.
- ababatan (I) has a CAS number of 1192491-61-4 and its chemical name is [(1R,2S,5R)-2-(aminocarbonyl)-7-oxo-1,6-diazabicyclo[ 3.2.1] octane-6-yl] sodium sulfate, the structural formula is as follows:
- intermediate VII (2S, 5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2. 1] Octane-2-carboxamide
- intermediate VIII 5R-benzyloxyaminopiperidine-2S-formate oxalate.
- Compound VII is debenzylated under different palladium carbon catalyzed by different reducing agents (such as hydrogen, triethylsilane, sodium formate, hydrazine hydrate), sulphur trioxide complex sulfated, ammonium salted, ion exchange prepared abiftam ( I), see Reaction Route 1.
- different reducing agents such as hydrogen, triethylsilane, sodium formate, hydrazine hydrate
- sulphur trioxide complex sulfated such as sodium formate, hydrazine hydrate
- ammonium salted ion exchange prepared abiftam ( I), see Reaction Route 1.
- the patent documents CN103649051A, CN105294690A use the amidation cycle after the amidation, using 5R-benzyloxyaminopiperidine-2S-formate oxalate (VIII) as raw material, ammonia ammonia solution or ammonia alcohol solution amide
- VIII 5R-benzyloxyaminopiperidine-2S-formate oxalate
- the ammonium oxalate filter is removed by filtration, the ammonium oxalate filter cake is washed with methanol, the obtained methanol solution is concentrated, the product is extracted with toluene, and the solvent is recrystallized to obtain (2S,5R)-5-benzyloxyaminopiperidine-2-carboxamide.
- the amidation reaction is cumbersome, and the urethane-9-mercaptomethyl chloroformate protection reagent used in the cyclic urea hydrolysis is expensive, and the 9-mercaptomethyl chloroformate and the carbonyl diimidazole provide only one carbonyl group, and the reaction atom economy Poor property, not conducive to environmental protection and cost reduction; and the use of (2S,5R)-5-benzyloxyaminopiperidine-2-carboxamide, without piperidine ring amino group protection, directly with triphosgene, carbonyl diimidazole Low yield (50-56%), no industrial value.
- the (2S,5R)-6-benzyloxy-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate obtained after cyclic urea formation has low activity and cannot be directly used.
- Ammonia methanol solution amidation requires hydrolysis of the ester group to a carboxyl group, and then activates the carboxyl group as an acid anhydride. After that, it can be effectively amidated, the operation process is cumbersome, and the atomic economy is poor, which is not conducive to environmental protection and industrial production.
- the raw material of the method uses N-protected L-pyroglutamic acid ester, trimethylsulfoxonium sulfoxide and methanesulfonic acid at a high price, and uses dimethyl sulfoxide as a solvent, and the post-treatment produces a large amount of waste water, which is poor in environmental protection and additionally The yield is low (59%).
- U.S. Patent No. US20140275001 provides a further synthesis of 5R-benzyloxyaminopiperidine-2S-formate (VIII free form) (see Scheme 4), the technical solution of which is still N-protected L-focus Glutamate is the starting material, and trimethyl iodide sulfoxide is opened to increase the carbon chain; the difference is that the US20140275001 patent document first uses a ruthenium catalyst to close the ring, and chiral reduction of the carbonyl group to obtain an S-configuration alcohol.
- the present invention provides a simple preparation method of avivatan.
- the preparation method has the advantages of simple preparation steps, simple route, easy operation, low starting material price, no expensive palladium carbon catalyst, low cost, less “three wastes” emission, high atomic utilization rate, economical and environmental protection, and high yield per step. It is conducive to the industrial production of Abadabatan.
- a method for preparing avivatan comprising the steps of:
- the compound of formula II is the same as R in the compound of formula III and is one of methyl, ethyl, isopropyl, n-propyl, t-butyl, n-butyl, isobutyl or benzyl;
- the PG in the compound is one of methoxymethyl, benzyloxymethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triethylsilyl or triisopropylsilyl.
- R, PG in the compound of formula IV have the same meaning as R and PG in the compound of formula III;
- the O-protected hydroxylamine hydrochloride salt in step (1) is methoxymethylhydroxylamine hydrochloride, benzyloxymethylhydroxylamine hydrochloride, tert-butyldimethylsilyl Hydroxylamine hydrochloride, tert-butyldiphenylsilylhydroxylamine hydrochloride, triethylsilylhydroxylamine hydrochloride, triisopropylsilylhydroxylamine hydrochloride; the O-protected hydroxylamine hydrochloride and The molar ratio of the compound of formula II is from 0.9 to 1.5:1.
- the solvent a in the step (1) is methanol, ethanol, propanol, butanol, ethyl acetate, tetrahydrofuran, acetonitrile, dichloromethane, chloroform, 1,2-dichloroethane, benzene. Or a combination of two or more of toluene; the mass ratio of the solvent a to the compound of the formula II is from 3 to 15:1; preferably, the mass ratio of the solvent a to the compound of the formula II is from 6 to 10: 1.
- the base a in the step (1) is an inorganic base or an organic base; preferably, the inorganic base is potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate or calcium hydrogencarbonate.
- the organic base being one or a combination of two of triethylamine or tri-n-butylamine; the base a and the compound of formula II
- the mass ratio is 0.5-1.5:1.
- the condensation reaction temperature in the step (1) is from 30 to 80 ° C; preferably, the condensation reaction temperature is from 30 to 60 ° C.
- the reaction time is 2-5 hours.
- the concentrated sulfuric acid in the step (2) is a sulfuric acid having a mass fraction of 95-98%, and the molar ratio of the concentrated sulfuric acid to the compound of the formula III is (3.0-6.0): 1; preferably, the Concentrated sulfuric acid is a sulfuric acid having a mass fraction of 98%.
- the present invention uses concentrated sulfuric acid and a substrate to form a salt in order to increase the selectivity of reduction.
- the mass ratio of the ethyl acetate to the compound of the formula III in the step (2) is from 5 to 20:1; preferably, the mass ratio of the ethyl acetate to the compound of the formula III is from 10 to 14:1.
- the use of ethyl acetate in the present invention facilitates stratification with the aqueous phase for post-treatment, and the resulting product of formula IV has a greater solubility in ethyl acetate.
- the reducing agent in the step (2) is sodium borohydride, sodium tricyanoborohydride, sodium triacetoxyborohydride, sodium tripropionyl borohydride, potassium borohydride, dicyandiamide.
- the reduction reaction temperature in the step (2) is (-30) - (-10) °C.
- the reaction time is 2-8 hours.
- the method of chiral resolution in the step (2) can be carried out in accordance with the prior art.
- the solvent b in the step (3) is water, methanol, ethanol, propanol, butanol, ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane, benzene or toluene.
- the mass ratio of the solvent b to the compound of the formula IV is from 3 to 12:1; and the mass ratio of the solvent b to the compound of the formula IV is from 3 to 6:1.
- the base b in the step (3) is one or two of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, calcium carbonate, potassium hydrogencarbonate or sodium hydrogencarbonate. Combination of the compounds; the molar ratio of the base b to the compound of formula IV is from 1.5 to 4.0:1.
- the hydrolysis reaction temperature in the step (3) is from 10 to 100 ° C; preferably, the hydrolysis reaction temperature is from 20 to 50 ° C.
- the reaction time is 2-7 hours.
- the solvent c in the step (4) is dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, methoxy One or a combination of two or more of cyclopentane or toluene; the mass ratio of the solvent c to the compound of the formula V is from 4 to 30:1; preferably, the mass ratio of the solvent c to the compound of the formula V is 18-30:1.
- the base c in the step (4) is one or two of trimethylamine, triethylamine, tri-n-butylamine, diisopropylethylamine, potassium carbonate, sodium carbonate or calcium carbonate.
- the above combination; the molar ratio of the base c to the compound of the formula V is from 3.0 to 8.0:1.
- the catalyst in the step (4) is one or a combination of two or more of N,N-dimethylformamide, pyridine or 4-dimethylaminopyridine; the quality of the catalyst is 0.1 to 5.0% by mass of the compound of formula V.
- the molar ratio of the solid phosgene, diphosgene or phosgene to the compound of the formula V in the step (4) is from 0.6 to 5.0:1; preferably, the solid phosgene and the compound of the formula V are The molar ratio is from 1.2 to 2.0:1, the molar ratio of the diphosgene to the compound of the formula V is from 1.0 to 2.5:1, and the molar ratio of the phosgene to the compound of the formula V is from 2.0 to 4.0:1.
- the ammonia in the step (4) is an alcohol solution using ammonia gas, ammonia gas, a tetrahydrofuran solution of ammonia gas, an acetonitrile solution of ammonia gas or an ammonia water; the alcohol solution of the ammonia gas
- concentration of ammonia in tetrahydrofuran solution, ammonia in acetonitrile or ammonia in ammonia is 5-20%.
- the molar ratio of said ammonia to the compound of formula V in step (4) is from 1.0 to 6.0:1.
- the temperature of the cyclic urea hydrolysis, the acid chloride and the amidation reaction in the step (4) is -20 to 60 ° C; preferably, the temperature of the cyclic urea hydrolysis, the acid chloride and the amidation reaction are both 10-30 ° C.
- the reaction time is 1-8 hours.
- the solvent d in the step (5) is water, isopropanol, isobutanol, ethyl acetate, dichloromethane, chloroform, 1,2-dichloroethane or isobutyl methyl ketone.
- the mass ratio of the solvent d to the compound of the formula VI is from 4 to 20:1; preferably, the mass ratio of the solvent d to the compound of the formula VI is from 4 to 8:1.
- the base d in the step (5) is one of trimethylamine, triethylamine, tri-n-butylamine or diisopropylethylamine; the molar ratio of the base d to the compound of the formula VI It is 0.2-0.7:1.
- the deprotecting agent when the PG in the compound of the formula VI is a non-silicon protecting group, the deprotecting agent is a sulfur trioxide trimethylamine complex, a sulfur trioxide triethylamine complex or a trioxide.
- the deprotecting group reagent is fluorotetrabutylammonium; the molar ratio of the deprotecting group reagent to the compound of the formula VI is 1.0. -3.0:1.
- the reagent for the sulfation in the step (5) is one of a sulfur trioxide trimethylamine complex, a sulfur trioxide triethylamine complex or a sulfur trioxide pyridine complex;
- the molar ratio of the reagent used for esterification to the compound of formula VI is from 1.0 to 3.0:1.
- the salt forming reagent used in the tetrabutylammonium salt formation reaction in the step (5) is tetrabutylammonium acetate or fluorotetrabutylammonium; the salt forming reagent used in the tetrabutylammonium salt formation reaction
- the molar ratio to the compound of formula VI is from 0.5 to 2:1.
- the deprotection group, the sulfation and the tetrabutylammonium salt in the step (5) are carried out in a "one-pot method", and the reaction temperature is 0-60 ° C; preferably, the reaction temperature is Both are 10-30 ° C.
- the reaction time is 1-8 hours.
- the reagent for ion exchange is sodium isooctanoate
- the molar ratio of the reagent for ion exchange to the compound of the formula VII is from 1.5 to 3.0:1.
- the ion exchange reaction temperature in the step (6) is 0 to 50 ° C; preferably, the ion exchange reaction temperature is 10 to 40 ° C.
- the reaction time is 1-5 hours.
- the method of ion exchange in the step (6) may be carried out in accordance with the prior art.
- the invention uses the piperidin-5-one-2S-formate II as a raw material to prepare a compound of the formula III 5-substituted oxyiminopiperidyl by condensation reaction with O-protected hydroxylamine hydrochloride in the presence of an alkaline reagent.
- O-non-benzyl-protecting hydroxylamine hydrochloride is used in the present invention, and the obtained intermediate (2S,5R)-6-substitutedoxy-7-oxo-1,6-diaza heterocycle [3.2.1 ]
- Octane-2-carboxamide is deprotected in an acidic environment, sulfated and tetrabutylammonium is formed into a "one-pot method", the steps are simple, and the reagents for protecting group reagents and sulfate esterification can be the same species.
- the method for removing the non-benzyl protecting group used in the present invention does not require the use of expensive trimethylsulfoxonium iodide or -9-mercaptomethyl chloroformate (FMOC).
- Raw materials such as -Cl), carbonyldiimidazole and 10% palladium carbon reduce the residual of heavy metals, improve product quality and further reduce costs.
- a specific concentration of concentrated sulfuric acid is selected in the step (2) to combine with the substrate to form a salt, so as to increase the selectivity of the reduction reaction.
- the “one-pot method” designed by the “one-pot method”, that is, the cyclic urea-acid chloride-amidation reaction “one-pot method” is completed, and the steps are simple, and the traditional method is avoided, and the amidation treatment is complicated. Problems such as high price of protective reagents for cyclic urea hydrolysis and poor economics of reaction atoms;
- the preparation method of the ababatam of the invention has simple steps, simple route, easy operation, low starting material price, no expensive palladium carbon catalyst, low cost, and “three wastes”. "Low emissions, high atomic utilization, economic and environmental protection, and high yields in each step are conducive to the industrial production of Avocabatan.
- Figure 1 is a 1 H-NMR chart of 5R-methoxymethyloxyaminopiperidine-2S-formic acid methyl oxalate (IV 1 ) obtained in the step (2) of Example 1.
- V 1 5R-methoxymethyloxyaminopiperidine-2S-carboxylic acid
- Figure 3 is a (2S,5R)-6-methoxymethyloxy-7-oxo-1,6-diazacyclo[3.2.1]octane-2 obtained in the step (4) of Example 1.
- Figure 4 is the ⁇ [(2S,5R)-2-carbamoyl-7-oxo-1,6-diazacyclo[3.2.1]octane-6-yl group obtained in the step (5) of Example 1.
- Fig. 5 is a 1 H-NMR chart of avivatan (I) obtained in the step (6) of Example 1.
- Fig. 6 is a 13 C-NMR chart of avivatan (I) obtained in the step (6) of Example 1.
- reaction process and product purity were monitored by gas phase or liquid chromatography, and the optical purity (area ratio %) was measured by a liquid chromatograph equipped with a chiral column (ES-OVS, 150 mm ⁇ 4.6 mm, Agilent), and the calculation was performed. Rate and purity ee% value.
- 2-Dichloroethane was extracted twice, 50 g of 1,2-dichloroethane each time, and the organic layers were combined and washed twice with saturated brine, 25 g each time. After recovering the solvent from the organic phase, it was distilled under reduced pressure to give 31.3 g of pale-yellow liquid 5-methoxymethyloxyiaminopiperidine-2S-carboxylic acid methyl ester with a purity of 99.8% and a yield of 96.5%.
- Step (2) Preparation of 5R-methoxymethyloxyaminopiperidine-2S-formic acid methyl oxalate (IV 1 )
- the reaction mixture was slowly added to 200 g of 10% aqueous ammonia, and the layers were separated, and the organic layer was washed twice with 25 g portions.
- the organic phase was concentrated to recover a solvent, and then 80 g of ethyl acetate, 40 g of methanol, 11.5 g (0.09 mol) of oxalic acid dihydrate was added to the residue, and the mixture was heated to 45 ° C, stirred for 1 hour, then cooled and filtered.
- the filter cake was washed first with 60 g of a mixture of ethyl acetate/methanol (2:1) and then washed with 50 g of ethyl acetate.
- the nuclear magnetic data of the obtained product are as follows: 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ : 1.39 (m, 1H), 1.64 (m, 1H), 1.85 (m, 1H), 2.12 (m, 1H), 2.62 ( t, 1H), 3.06 (m, 1H), 3.36 (d, 1H), 3.74 (s, 3H), 3.93 (q, 1H), 4.58 (s, 2H), 7.26-7.38 (m, 5H).
- Step (3) Preparation of 5R-methoxymethyloxyaminopiperidine-2S-carboxylic acid (V 1 )
- the nuclear magnetic data of the obtained product are as follows: 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ : 1.25 (m, 1H), 1.44 (m, 1H), 1.79 (m, 1H), 2.10 (m, 1H), 3.02 ( m, 1H), 3.07 (br, 1H), 3.21 (d, 1H), 4.57 (s, 2H), 6.75 (s, 1H), 7.29-7.34 (m, 5H).
- thermometer To a 500 ml four-necked flask equipped with a stirring, a thermometer was charged with 200 g of tetrahydrofuran, 10.2 g (0.05 mol) of 5-methoxymethyloxyaminopiperidine-2S-carboxylic acid prepared by the method of the step (3), 50 g. Diisopropylethylamine, 0.1 g of N,N-dimethylformamide, cooled, at a temperature of -10-0 ° C, a mixed solution of 23.8 g (0.08 mol) of solid phosgene and 80 g of tetrahydrofuran was added dropwise, and the mixture was dropped. The reaction was stirred at -20 ° C for 4 hours.
- the nuclear magnetic data of the obtained product are as follows: 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ : 1.63 (m, 2H), 1.84 (m, 1H), 2.06 (m, 1H), 2.90 (s, 2H), 3.62 ( Br, 1H), 3.68 (d, 1H), 4.94 (q, 1H), 4.58 (s, 2H), 7.28-7.46 (m, 5H).
- the reaction liquid was poured into 150 g of dichloromethane and 150 g of ice water mixture, and acetic acid was added to adjust the system.
- the pH was 3.5-2.5, the layers were separated, and the aqueous layer was extracted twice with dichloromethane, 50 g each time.
- the organic phase was combined and washed twice with a saturated sodium chloride solution, 20 g each time. After the organic solvent was recovered, the residue was recrystallized from 50 g of dichloromethane-methyl isobutyl ketone (1:3 by volume).
- the nuclear magnetic data of the obtained product are as follows: 1 H-NMR (400 MHz, DMSO-d 6 ) ⁇ : 0.97 (t, 12H), 1.42 (m, 8H), 1.64 (m, 9H), 1.84 (m, 1H), 2.12 ( m, 1H), 2.35 (m, 1H), 2.83 (d, 1H), 3.27 (m, 9H), 3.89 (d, 1H), 4.30 (s, 1H), 5.83 (s, 1H), 6.66 (s) , 1H).
- the nuclear magnetic data of the obtained product are as follows: 1 H-NMR (400 MHz, D 2 O) ⁇ : 1.69 (m, 1H), 1.83 (m, 1H), 1.96 (m, 1H), 2.10 (m, 1H), 3.00 (d) , 1H), 3.22 (d, 1H), 3.96 (d, 1H), 4.09 (q, 1H).
- tert-Butyldimethylsilylhydroxylamine hydrochloride 25 g of triethylamine, stirred at 38-40 ° C for 5 hours, cooled to 20-25 ° C, added 100 g of water, layered, and the aqueous layer was extracted with dichloromethane Two times, 50 g of dichloromethane each time, the organic layers were combined and washed twice with saturated brine, 25 g each time. After recovering the solvent from the organic phase, 41.0 g of pale yellow liquid 5-t-butyldimethylsilyloxyiminopiperidine-2S-formic acid methyl ester was obtained by distillation under reduced pressure. The purity of the mixture was 99.9%, and the yield was 95.6%.
- Step (2) Preparation of 5R-tert-butyldimethylsilyloxyaminopiperidine-2S-formic acid methyl oxalate (IV 2 )
- the reaction mixture was slowly added to 200 g of 10% aqueous ammonia, and the layers were separated, and the organic layer was washed twice with 25 g portions.
- the organic phase was concentrated to recover a solvent, and then 80 g of ethyl acetate, 40 g of methanol, 11.5 g (0.09 mol) of oxalic acid dihydrate was added to the residue, and the mixture was heated to 45 ° C, stirred for 1 hour, then cooled and filtered.
- the filter cake was washed first with 60 g of a mixture of ethyl acetate/methanol (2:1) and then washed with 50 g of ethyl acetate.
- Step (3) Preparation of 5R-tert-butyldimethylsilyloxyaminopiperidine-2S-carboxylic acid (V 1 )
- Methylsilyloxy-7-oxo-1,6-diazacyclo[3.2.1]octane-2-carboxamide 5.5 g of triethylamine, 39.0 g (0.15 mol) of fluorotetrabutyl Ammonium, at 10-15 ° C, 22.5 g (0.12 mol) of trimethylamine trioxide complex was added, stirred at 15-20 ° C for 5 hours, the reaction liquid was poured into 150 g of dichloromethane and 100 g of ice water mixture Add acetic acid to adjust the pH of the system to 3.5-2.5, layer, and extract the water layer twice with dichloromethane, 50 g each time.
- a method for preparing avivatan comprises the following steps:
- step (1) of Embodiment 1 the difference is:
- the condensation reaction conditions are: stirring at 20-25 ° C for 8 hours;
- condensation reaction temperature has an important influence on the yield of the target product.
- Step (2) Preparation of 5R-methoxymethyloxyaminopiperidine-2S-formic acid methyl oxalate (IV 1 )
- step (2) of embodiment 1 the difference is:
- the concentration of concentrated sulfuric acid having a mass concentration of 98% is 20.0 (0.2 mol);
- Step (3) Preparation of 5R-methoxymethyloxyaminopiperidine-2S-carboxylic acid (V 1 )
- step (3) of Embodiment 1 the difference is:
- the hydrolysis reaction condition is: stirring reaction at 70-75 ° C for 3 hours;
- step (4) of embodiment 1 the difference is:
- the amount of solid phosgene added was: 14.9 g (0.05 mol);
- step (5) of embodiment 1 the difference is:
- reaction temperature of the deprotecting group, the sulfation, and the tetrabutylammonium salt has an important influence on the yield of the product.
- step (6) of Embodiment 1 the difference is:
- the ion exchange reaction conditions are: stirring at 40-45 ° C for 3 hours;
Abstract
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Claims (10)
- 一种阿维巴坦的制备方法,包括步骤:(1)于溶剂a中,在碱a催化下,式Ⅱ化合物和O-保护基羟胺盐酸盐经缩合反应制备式Ⅲ化合物;其中,式Ⅱ化合物和式Ⅲ化合物中的R相同,为甲基、乙基、异丙基、正丙基、叔丁基、正丁基、异丁基或苄基中的一种;式Ⅲ化合物中的PG为甲氧基甲基、苄氧基甲基、叔丁基二甲基硅基、叔丁基二苯基硅基、三乙基硅基或三异丙基硅基中的一种;(2)在浓硫酸、乙酸乙酯存在下,式Ⅲ化合物经还原剂还原、手性拆分得到式IV化合物;其中,式IV化合物中的R、PG与式Ⅲ化合物中的R、PG具有相同的含义;(3)于溶剂b中,式IV化合物在碱b的存在下水解得到式V化合物;其中,式V化合物中的PG与式IV化合物中的PG具有相同的含义;(4)于溶剂c、碱c和催化剂存在下,式V化合物和光气、固体光气或双光气经环脲化、酰氯化反应,再和氨经酰胺化反应得到式Ⅵ化合物;其中,式Ⅵ化合物中的PG与式V化合物中的PG具有相同的含义;(5)于溶剂d中,在碱d的催化下,式Ⅵ化合物经脱保护基试剂脱保护基、硫酸酯化、四丁基铵化成盐得到式VII化合物;(6)式VII化合物经离子交换制得阿维巴坦(I)。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(1)中,包括以下条件中任一项或多项:A、所述O-保护基羟胺盐酸盐为甲氧基甲基羟胺盐酸盐、苄氧基甲基羟胺盐酸盐、叔丁基二甲基硅基羟胺盐酸盐、叔丁基二苯基硅基羟胺盐酸盐、三乙基硅基羟胺盐酸盐、三异丙基硅基羟胺盐酸盐;所述O-保护基羟胺盐酸盐与式Ⅱ化合物的摩尔比为0.9-1.5:1;B、所述溶剂a为甲醇、乙醇、丙醇、丁醇、乙酸乙酯、四氢呋喃、乙腈、二氯甲烷、氯仿、1,2-二氯乙烷、苯或甲苯中的一种或两种以上的组合;所述溶剂a与式Ⅱ化合物的质量比为3-15:1;优选的,所述溶剂a与式Ⅱ化合物的质量比为6-10:1;C、所述碱a为无机碱或有机碱;优选的,所述无机碱为碳酸钾、碳酸钠、碳酸钙、碳酸氢钾、碳酸氢钠、碳酸氢钙、醋酸钾、醋酸钠或醋酸钙中的一种或两种以上的组合,所述有机碱为三乙胺或三正丁胺中的一种或两种的组合;所述碱a与式Ⅱ化合物的质量比为0.5-1.5:1。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(1)中所述缩合反应温度为30-80℃;优选的,所述缩合反应温度为30-60℃。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(2)中所述浓硫酸为质量分数95-98%的硫酸,所述浓硫酸与式Ⅲ化合物的摩尔比为(3.0-6.0):1;优选的,所述浓硫酸为质量分数98%的硫酸。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(2)中,包括以下条件中任一项或多项:A、所述乙酸乙酯与式Ⅲ化合物的质量比为5-20:1;优选的,乙酸乙酯与式Ⅲ化合物的质量比为10-14:1;B、所述还原剂为硼氢化钠、三氰基硼氢化钠、三乙酰氧基硼氢化钠、三丙酰氧基硼氢化钠、硼氢化钾、三氰基硼氢化钾、三乙酰氧基硼氢化钾或三丙酰氧基硼氢化钾;所述还原剂与式Ⅲ化合物的摩尔比为2.0-4.0:1;C、所述还原反应温度为(-30)-(-10)℃。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(3)中,包括以下条件中任一项或多项:A、所述溶剂b为水、甲醇、乙醇、丙醇、丁醇、乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷、苯或甲苯中的一种或两种以上的组合;所述溶剂b与式IV化合物的质量比为3-12:1;所述溶剂b与式IV化合物的质量比为3-6:1;B、所述碱b是氢氧化钠、氢氧化钾、氢氧化锂、碳酸钾、碳酸钠、碳酸钙、碳酸氢钾或碳酸氢钠中的一种或两种的组合;所述碱b和式IV化合物的摩尔比为1.5-4.0:1;C、所述水解反应温度为10-100℃;优选的,所述水解反应温度为20-50℃。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(4)中,包括以下条件中任一项或多项:A、所述溶剂c为二氯甲烷、1,2-二氯乙烷、三氯甲烷、四氯化碳、乙腈、四氢呋喃、2-甲基四氢呋喃、甲氧基环戊烷或甲苯中的一种或两种以上的组合;所述溶剂c与式V化合物的质量比为4-30:1;优选的,所述溶剂c与式V化合物的质量比为18-30:1;B、所述碱c是三甲胺、三乙胺、三正丁胺、二异丙基乙胺、碳酸钾、碳酸钠或碳酸钙中的一种或两种以上的组合;所述碱c与式V化合物的摩尔比为3.0-8.0:1;C、所述催化剂为N,N-二甲基甲酰胺、吡啶或4-二甲氨基吡啶中的一种或两种以上的组合;所述催化剂的质量是式V化合物质量的0.1-5.0%;D、所述固体光气、双光气或光气和式V化合物的摩尔比为0.6-5.0:1;优选的,所述固体光气和式V化合物的摩尔比为1.2-2.0:1,所述双光气和式V化合物的摩尔比为1.0-2.5:1,所述光气和式V化合物的摩尔比为2.0-4.0:1;E、所述氨是使用氨气、氨气的醇溶液、氨气的四氢呋喃溶液、氨气的乙腈溶液或氨水中的一种;所述氨气的醇溶液、氨气的四氢呋喃溶液、氨气的乙腈溶液或氨水中氨气的质量浓度为5-20%;F、所述氨和式V化合物的摩尔比为为1.0-6.0:1;G、所述环脲化、酰氯化和酰胺化反应温度均为-20-60℃;优选的,所述环脲化、酰氯 化和酰胺化反应温度均为10-30℃。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(5)中,包括以下条件中任一项或多项:A、所述溶剂d为水、异丙醇、异丁醇、乙酸乙酯、二氯甲烷、氯仿、1,2-二氯乙烷或异丁基甲基酮中的一种或两种以上的组合;所述溶剂d与式Ⅵ化合物的质量比为4-20:1;优选的,所述溶剂d与式Ⅵ化合物的质量比为4-8:1;B、所述碱d为三甲胺、三乙胺、三正丁胺或二异丙基乙胺中的一种;所述碱d与式Ⅵ化合物的摩尔比为0.2-0.7:1;C、当式Ⅵ化合物中的PG为非硅保护基时,脱保护基试剂为三氧化硫三甲胺复合物、三氧化硫三乙胺复合物或三氧化硫吡啶复合物中的一种;当式Ⅵ化合物中的PG为含硅保护基时,脱保护基试剂为氟代四丁基铵;所述脱保护基试剂与式Ⅵ化合物的摩尔比为1.0-3.0:1;D、所述硫酸酯化所用试剂为三氧化硫三甲胺复合物、三氧化硫三乙胺复合物或三氧化硫吡啶复合物中的一种;所述硫酸酯化所用试剂与式Ⅵ化合物的摩尔比为1.0-3.0:1;E、四丁基铵化成盐反应所用成盐试剂为四丁基乙酸铵或氟代四丁基铵;所述四丁基铵化成盐反应所用成盐试剂与与式Ⅵ化合物的摩尔比为0.5-2:1。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(5)中所述脱保护基、硫酸酯化和四丁基铵化成盐“一锅法”进行,反应温度均为0-60℃;优选的,所述反应温度均为10-30℃。
- 根据权利要求1所述的阿维巴坦的制备方法,其特征在于,步骤(6)中,包括以下条件中任一项或多项:A、所述离子交换所用试剂为异辛酸钠,所述离子交换所用试剂和式VII化合物的摩尔比为1.5-3.0:1;B、所述离子交换反应温度为0-50℃;优选的,所述离子交换反应温度为10-40℃。
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CN109956941A (zh) | 2019-07-02 |
KR102238179B1 (ko) | 2021-04-09 |
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EP3766869B1 (en) | 2023-05-10 |
US20210332060A1 (en) | 2021-10-28 |
KR20190082194A (ko) | 2019-07-09 |
AU2018344099B2 (en) | 2020-01-02 |
JP6771097B2 (ja) | 2020-10-21 |
US11208417B2 (en) | 2021-12-28 |
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CA3042923A1 (en) | 2019-06-25 |
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AU2018344099A1 (en) | 2019-07-11 |
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