CN114478273A - Preparation method of metahydroxylamine bitartrate - Google Patents
Preparation method of metahydroxylamine bitartrate Download PDFInfo
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- CN114478273A CN114478273A CN202210061753.8A CN202210061753A CN114478273A CN 114478273 A CN114478273 A CN 114478273A CN 202210061753 A CN202210061753 A CN 202210061753A CN 114478273 A CN114478273 A CN 114478273A
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- FEWJPZIEWOKRBE-UHFFFAOYSA-M 3-carboxy-2,3-dihydroxypropanoate Chemical compound OC(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-M 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 238000003756 stirring Methods 0.000 claims abstract description 38
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- 239000002904 solvent Substances 0.000 claims abstract description 16
- 238000001914 filtration Methods 0.000 claims abstract description 13
- 229940125782 compound 2 Drugs 0.000 claims abstract description 12
- 229940125898 compound 5 Drugs 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 10
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 9
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003054 catalyst Substances 0.000 claims abstract description 8
- 229940125904 compound 1 Drugs 0.000 claims abstract description 7
- 229940126214 compound 3 Drugs 0.000 claims abstract description 7
- USZLCYNVCCDPLQ-UHFFFAOYSA-N hydron;n-methoxymethanamine;chloride Chemical compound Cl.CNOC USZLCYNVCCDPLQ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000003513 alkali Substances 0.000 claims abstract description 5
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 4
- 235000002906 tartaric acid Nutrition 0.000 claims abstract description 4
- 239000011975 tartaric acid Substances 0.000 claims abstract description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 15
- 238000001816 cooling Methods 0.000 claims description 15
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 14
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 12
- 238000010438 heat treatment Methods 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000004809 thin layer chromatography Methods 0.000 claims description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 8
- 229910052763 palladium Inorganic materials 0.000 claims description 7
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- 238000004440 column chromatography Methods 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 238000003747 Grignard reaction Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- 239000008346 aqueous phase Substances 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 238000005406 washing Methods 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract 1
- 238000000926 separation method Methods 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- VENXSELNXQXCNT-IJYXXVHRSA-N metaraminol bitartrate Chemical compound [H+].[H+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O.C[C@H](N)[C@H](O)C1=CC=CC(O)=C1 VENXSELNXQXCNT-IJYXXVHRSA-N 0.000 description 2
- 229960002984 metaraminol bitartrate Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 2
- 238000001308 synthesis method Methods 0.000 description 2
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 208000001953 Hypotension Diseases 0.000 description 1
- 208000011861 acute hypotension Diseases 0.000 description 1
- 239000000695 adrenergic alpha-agonist Substances 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000002360 explosive Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- MCSAJNNLRCFZED-UHFFFAOYSA-N nitroethane Chemical compound CC[N+]([O-])=O MCSAJNNLRCFZED-UHFFFAOYSA-N 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
- C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/41—Preparation of salts of carboxylic acids
- C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a preparation method of meta-hydroxylamine bitartrate, which comprises the following steps in sequence: reacting the compound 1 with N, O-dimethyl hydroxylamine hydrochloride to obtain a compound 2, and adding alkali in the reaction process; reacting the compound 2 obtained in the step with a compound 3 to obtain a compound 4; reacting the compound 4 obtained in the step with aluminum isopropoxide to obtain a compound 5; adding the compound 5 obtained in the step into a solvent, adding a metal catalyst, introducing hydrogen to remove benzyl to obtain m-hydroxylamine, adding tartaric acid, stirring and filtering to obtain m-hydroxylamine bitartrate. The method has the advantages of short route, good chiral selectivity by using aluminum isopropoxide for asymmetric reduction, avoiding the separation of isomers and saving cost.
Description
Technical Field
The invention belongs to the technical field of medicine production, and particularly relates to a preparation method of metahydroxylamine bitartrate.
Background
Metaraminol Bitartrate (Metaraminol Bitartrate) is a Bitartrate salt of metahydroxylamine, is an alpha-adrenergic receptor agonist developed by Fresenius Kabi company in the united states, mainly acts on an alpha receptor, is suitable for treating shock at the early stage and preventing acute hypotension during intraspinal stasis anesthesia.
CN103739504 reports a synthesis method of meta-hydroxylamine bitartrate as follows:
nitroethane used in the route belongs to flammable and explosive materials, is dangerous and is not suitable for production amplification. And the route has no chiral selectivity, and the chiral resolution cost is very high.
CN107311875A reports another synthesis method of m-hydroxylamine bitartrate:
the route has long steps, and the route also has no chiral selectivity, so the chiral resolution cost is high.
As can be seen from the above review, the existing synthetic strategies for meta-hydroxylamine bitartrate have the defects of no chiral selectivity and high chiral resolution cost.
Disclosure of Invention
The present invention aims to provide a method for preparing meta-hydroxylamine bitartrate, which solves the problems in the background art.
The technical scheme adopted by the invention for solving the technical problems is as follows: a preparation method of meta-hydroxylamine bitartrate comprises the following steps in sequence:
s1, structural formula
The compound 1 reacts with N, O-dimethyl hydroxylamine hydrochloride in a solvent, and alkali is added in the reaction process to obtain the compound with the structural formula as shown in the specification
Compound 2 of (1);
s2, carrying out the stepsThe obtained compound 2 has the structural formula
The compound 3 is subjected to a Grignard reaction in a solvent to obtain a compound with a structural formula
Compound 4 of (1);
s3, adding the compound 4 obtained in the step into a solvent, and reacting with a reducing agent aluminum isopropoxide to obtain a compound with a structural formula shown in the specification
Compound 5 of (1);
s4, adding the compound 5 obtained in the previous step into a solvent, adding a palladium catalyst, introducing hydrogen to remove benzyl to obtain m-hydroxylamine, adding tartaric acid, stirring and filtering to obtain m-hydroxylamine bitartrate.
The solvent of the preparation method of the m-hydroxylamine bitartrate is one of DCM, THF, MTBE, toluene and dioxane
In the preparation method of the meta-hydroxylamine bitartrate, the alkali is a conventional organic alkaline reagent, such as triethylamine, DBU, DIPEA and the like.
In the preparation method of the meta-hydroxylamine bitartrate, the palladium catalyst is one of palladium carbon and palladium hydroxide carbon.
Further, the step S1 specifically includes: adding 100ml of DCM into a reaction bottle, then adding 10g of the compound 1, stirring and cooling to 0-10 ℃, then dropwise adding 10g of liquid triethylamine, adding 6g N, O-dimethylhydroxylamine hydrochloride, keeping the temperature to 0-10 ℃, and stirring for 4 hours; after the TLC (thin layer chromatography) neutral control reaction is finished, 300ml of 1mol/L hydrochloric acid solution is dripped to adjust the pH value to be approximately equal to 1, and then the mixture is stirred, kept stand and layered; the lower organic phase was collected, dried over anhydrous sodium sulfate, then filtered, the filtrate was collected and concentrated to give a crude product, which was mixed with a sample and purified by column chromatography to give 10g of compound 2 in 80% yield as a pale yellow solid.
Further, the step S2 is specifically: to the reaction flask was added 70ml of THF, followed by addition of 20g of Compound 2, followed by stirring; cooling to 0-10 ℃ while stirring, dropwise adding 200ml of 1mol/L THF solution of the compound 3, heating to 20-30 ℃, and stirring for 4 hours; after TLC (thin layer chromatography) controlled reaction is finished, cooling to 0-10 ℃, dropwise adding 1mol/L diluted hydrochloric acid to adjust the pH to 1, stirring, and then standing for layering; collecting the upper organic layer, extracting the lower aqueous phase with MTBE, combining all organic layers, and washing with a saturated laboratory; adding anhydrous sodium sulfate, drying, filtering, concentrating the filtrate to obtain crude product, mixing with sample, and purifying by column chromatography to obtain 20g of white solid compound 4.
Still further, step S3 specifically includes: sequentially adding 200ml of isopropanol and 20g of compound 4 into a reaction bottle, then adding 10g of aluminum isopropoxide, heating to 70-80 ℃, and stirring for 4 hours; after TLC (thin layer chromatography) control reaction is finished, cooling to 20-30 ℃, adding into 200ml of 1mol/L hydrochloric acid, and extracting twice with MTBE; all organic phases were combined, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to give 18g of compound 5 as a pale yellow solid.
Still further, step S4 specifically includes: adding 20g of the compound 5 into a reaction bottle, adding 200ml of MeOH and 2g of palladium-carbon, performing hydrogen replacement for three times, stirring and heating to 40-50 ℃, introducing hydrogen, and stirring for 4 hours under the pressure of 1 Mpa; after the TLC (thin layer chromatography) control reaction is finished, filtering the reaction solution, dropwise adding a methanol (70ml) solution of 7.6g L-tartaric acid into the filtrate, heating to 50-60 ℃, and stirring for 2 hours; and cooling the reaction to 10-20 ℃, stirring for 2h, filtering and collecting a filter cake, and performing vacuum drying to obtain 16g of white solid m-hydroxylamine bitartrate.
The invention has the technical effects and advantages that: the preparation method has the advantages of short route, good chiral selectivity, avoidance of isomer resolution, reduction of resolution cost and suitability for large-scale production, and aluminum isopropoxide is used for asymmetric reduction.
Detailed Description
The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The invention discloses a preparation method of meta-hydroxylamine bitartrate, which comprises the following synthetic route:
wherein [ M ] is conventional organic alkaline reagent, such as triethylamine, DBU, DIPEA and the like; [ Pd ] is a palladium catalyst such as palladium on carbon, palladium on carbon hydroxide. The method comprises the following specific steps:
s1: has a structural formula of
The compound 1 reacts with N, O-dimethyl hydroxylamine hydrochloride in a solvent, and alkali is added in the reaction process to obtain the compound with the structural formula as shown in the specification
Compound 2 of (1).
The preparation steps of the compound 2 are as follows: adding 100ml of DCM into a reaction bottle, then adding 10g of the compound 1, stirring and cooling to 0-10 ℃, then dropwise adding 10g of liquid triethylamine, adding 6g N, O-dimethylhydroxylamine hydrochloride, keeping the temperature to 0-10 ℃, and stirring for 4 hours; after the TLC (thin layer chromatography) neutral control reaction is finished, 300ml of 1mol/L hydrochloric acid solution is dripped to adjust the pH value to be approximately equal to 1, and then the mixture is stirred, kept stand and layered; the lower organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was collected and concentrated to give a crude product, which was mixed with a sample and purified by column chromatography to give 10g of compound 2, 80% yield, as a pale yellow solid.
S2: the compound 2 obtained in the step is mixed with a compound with a structural formula shown in the specification
The compound 3 is subjected to a Grignard reaction in a solvent to obtain a compound with a structural formula
Compound 4 of (1).
Wherein the preparation steps of the compound 4 are as follows: THF (70ml) was added to the reaction flask, followed by addition of Compound 2(20g), followed by stirring. Stirring and cooling to 0-10 ℃. 200ml of a THF solution (1mol/L) of Compound 3 are added dropwise. Heating to 20-30 ℃, and stirring for 4 h. The reaction was completed by TLC (thin layer chromatography). Cooling to 0-10 ℃, and dropwise adding to 1mol/L dilute hydrochloric acid to adjust the pH to be approximately equal to 1. Stirring, and standing for layering. The upper organic layer was collected and the lower aqueous layer was extracted with MTBE, and all organic layers were combined and washed with a saturated laboratory. Adding anhydrous sodium sulfate, drying, filtering, concentrating the filtrate to obtain a crude product, mixing with a sample, and purifying by column chromatography to obtain 20g of compound 4 with yield of 70% as a white solid.
S3, adding the compound 4 into a solvent, and reacting with aluminum isopropoxide to obtain a compound with a structural formula
Compound (5) of (1).
Wherein the preparation steps of the compound 5 are as follows: isopropanol (200ml) was added to the reaction flask. Compound 4 (20 g). Aluminum isopropoxide (10g) was added. Heating to 70-80 ℃, and stirring for 4 h. The reaction was completed by TLC (thin layer chromatography). Cooling to 20-30 ℃, and adding into 1mol/L hydrochloric acid (200 ml). Extracted twice with MTBE. All organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give 18g of compound 5 in 90% yield as a pale yellow solid.
S4, adding the compound 5 into a solvent, adding a palladium catalyst, introducing hydrogen to remove benzyl to obtain m-hydroxylamine, adding tartaric acid, stirring and filtering to obtain m-hydroxylamine bitartrate.
Wherein the preparation steps of the compound meta-hydroxylamine bitartrate are as follows: to a reaction flask was added compound 5(20g), MeOH (200ml), palladium on carbon (2 g). And (3) replacing with hydrogen for three times, stirring and heating to 40-50 ℃, and introducing hydrogen under the pressure of 1 Mpa. Stirring for 4 h. The reaction was completed by TLC (thin layer chromatography). The reaction mixture was filtered, and a methanol (70ml) solution of L-tartaric acid (7.6g) was added dropwise to the filtrate. Heating to 50-60 ℃, and stirring for 2 h. And cooling the reaction to 10-20 ℃, and stirring for 2 h. Filtering, collecting filter cake, vacuum drying to obtain 16g m-hydroxylamine bitartrate with yield of 88% and white solid.
Example 2
The difference between the method for producing metahydroxylamine bitartrate disclosed in this example and example 1 is that toluene or dioxane was used as the solvent.
Example 3
The difference between the method for preparing metahydroxylamine bitartrate disclosed in this example and example 1 is that DBU or DIPEA is used as the base.
Example 4
The difference between the method for preparing metahydroxylamine bitartrate disclosed in this example and example 1 is that the palladium catalyst is palladium hydroxide on carbon.
The preparation method of meta-hydroxylamine bitartrate has good chiral selectivity.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (8)
1. A preparation method of meta-hydroxylamine bitartrate is characterized by comprising the following steps: comprises the following steps
S1, structural formula
The compound 1 reacts with N, O-dimethyl hydroxylamine hydrochloride in a solvent, and alkali is added in the reaction process to obtain the compound with the structural formula as shown in the specification
Compound 2 of (1);
s2 reaction of Compound 2 with a structural formula
The compound 3 is subjected to a Grignard reaction in a solvent to obtain a compound with a structural formula
Compound 4 of (1);
s3, adding the compound 4 into a solvent to react with aluminum isopropoxide to obtain a compound with a structural formula
Compound 5 of (1);
s4, putting the compound 5 into a solvent, adding a palladium catalyst, introducing hydrogen to remove benzyl to obtain m-hydroxylamine, adding tartaric acid, stirring and filtering to obtain m-hydroxylamine bitartrate.
2. The method of claim 1, wherein the solvent is one of DCM, THF, MTBE, methanol, isopropanol, toluene, dioxane.
3. The method of claim 2, wherein the base is one of triethylamine, DBU, and DIPEA.
4. The method of claim 3, wherein the palladium catalyst is one of palladium on carbon and palladium on carbon hydroxide.
5. The method for preparing meta-hydroxylamine bitartrate according to claim 2, 3 or 4, wherein the step S1 is specifically as follows:
adding DCM into a reaction bottle, adding the compound 1, stirring, cooling to 0-10 ℃, then dropwise adding liquid triethylamine, adding N, O-dimethylhydroxylamine hydrochloride, keeping the temperature to 0-10 ℃, and stirring for 4 hours;
after TLC (thin layer chromatography) medium control reaction is finished, dropwise adding hydrochloric acid solution to adjust the pH to 1, then stirring, standing and layering;
collecting lower organic phase, drying with anhydrous sodium sulfate, filtering, collecting filtrate, concentrating to obtain crude product, mixing with sample, and purifying by column chromatography to obtain light yellow solid compound 2.
6. The method for preparing meta-hydroxylamine bitartrate according to claim 5, wherein the step S2 specifically comprises:
adding THF into a reaction bottle, adding the compound 2 and stirring;
stirring and cooling to 0-10 ℃, dropwise adding a THF solution of the compound 3, heating to 20-30 ℃, and stirring for 4 hours;
after TLC (thin-layer chromatography) medium control reaction is finished, cooling to 0-10 ℃, dropwise adding dilute hydrochloric acid to adjust the pH to 1, stirring, and then standing for layering;
collecting the upper organic layer, extracting the lower aqueous phase with MTBE, combining all the organic layers, and washing with a saturated laboratory;
adding anhydrous sodium sulfate, drying, filtering, concentrating the filtrate to obtain crude product, mixing with sample, and purifying by column chromatography to obtain white solid compound 4.
7. The method for preparing meta-hydroxylamine bitartrate according to claim 6, wherein the step S3 specifically comprises:
sequentially adding isopropanol and the compound 4 into a reaction bottle, adding aluminum isopropoxide, heating to 70-80 ℃, and stirring for 4 hours;
after TLC (thin-layer chromatography) medium control reaction is finished, cooling to 20-30 ℃, adding into hydrochloric acid, and extracting twice with MTBE (methyl tert-butyl ether);
all organic phases were combined, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to give compound 5 as a pale yellow solid.
8. The method for preparing meta-hydroxylamine bitartrate according to claim 7, wherein the step S4 specifically comprises:
adding the compound 5, methanol and palladium carbon into a reaction bottle in sequence, replacing with hydrogen for three times, stirring and heating to 40-50 ℃, introducing hydrogen and stirring for 4 hours;
after TLC (thin layer chromatography) medium control reaction is finished, filtering the reaction solution, dropwise adding a methanol solution of L-tartaric acid into the filtrate, heating to 50-60 ℃, and stirring for 2 hours;
and cooling the reaction to 10-20 ℃, stirring for 2h, filtering and collecting a filter cake, and performing vacuum drying to obtain white solid metahydroxylamine bitartrate.
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| CN116332774A (en) * | 2023-03-29 | 2023-06-27 | 成都瑞尔医药科技有限公司 | Preparation method of high chiral purity meta-hydroxylamine bitartrate |
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