CN115232113A - Process for the preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ester salts - Google Patents

Process for the preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ester salts Download PDF

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CN115232113A
CN115232113A CN202210778032.9A CN202210778032A CN115232113A CN 115232113 A CN115232113 A CN 115232113A CN 202210778032 A CN202210778032 A CN 202210778032A CN 115232113 A CN115232113 A CN 115232113A
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牛华英
王景成
王志超
魏建成
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Shandong Zhitai Medical Technology Co ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
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Abstract

The invention belongs to the technical field of medical chemistry, and particularly relates to a preparation method of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic ester salt. The invention takes (S) -5-oxo piperidine-2-carboxylic ester as raw material, and prepares 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic ester salt through ketone-amine condensation, chiral reduction and resolution. The preparation method has simple process, stable yield and high chiral purity. The compound can be used for preparing avibactam sodium.

Description

Process for the preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ester salts
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a preparation method of a compound 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic ester salt.
Background
The invention discloses a preparation method of a compound, and the compound can be used as an intermediate of raw material medicines for preparing avibactam sodium.
Abamebactam sodium is a kind of beta-lactamase inhibitor depending on serine, and can be connected with the hydroxyl of the serine of the enzyme through the hydrolytic cleavage of self amido bond, so that the activity of the enzyme is lost. Therefore, the abamectin sodium has broad-spectrum antibacterial activity when being combined with various cephalosporin and carbapenem antibiotics, and particularly has remarkable activity on escherichia coli containing the ultra-broad-spectrum beta-lactamase, klebsiella pneumoniae, escherichia coli containing the excess AmpC enzyme and escherichia coli containing both the AmpC and the ultra-broad-spectrum beta-lactamase. It can effectively inhibit the activity of Ser-dependent enzymes in class A and class C.
5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ethyl ester, molecular formula: c 13 H 24 N 2 O 4 The structural formula is as follows:
Figure DEST_PATH_IMAGE001
the synthesis method of the disclosed compound comprises the following steps:
the synthesis method disclosed in patent CN 107540601B is as follows:
the method comprises the following steps:
Figure DEST_PATH_IMAGE002
the method takes N-protected L-pyroglutamic acid ester as a starting material, increases a carbon chain through trimethyl sulfoxide iodide ring opening, converts a carbonyl group into imine, removes a protecting group under an acidic condition, closes the ring under an alkaline condition, and finally obtains a product through reduction and chiral resolution by using a reducing agent.
In the above method, N-protected L-pyroglutamate is used as a starting material, and the reaction steps are 4 steps in total, and the method uses the expensive starting material and trimethyl sulfoxide iodide, and has a long reaction step.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention aims to provide a preparation method of a compound 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic ester salt. According to the invention, through the (S) -5-oxo-piperidine-2-carboxylic ester initial compound, the ketoamine condensation reaction is directly carried out, the use of trimethyl sulfoxide iodide is avoided, the preparation steps are shortened, and meanwhile, the source of raw materials is wider.
The technical scheme adopted by the invention for realizing the purpose is as follows:
the invention provides a preparation method of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic ester salt, which comprises the following steps:
(1) Adding ethyl acetate into the compound IV, mixing, stirring and dissolving, adding an amino compound for reaction, and then heating for reaction; after the reaction is finished, cooling to room temperature, washing an organic phase by using saturated salt solution, and then separating liquid; separating ethyl acetate layer, adding anhydrous sodium sulfate, drying, filtering, concentrating the filtrate to 0.4 times of original volume to obtain ethyl acetate concentrated solution of oxime compound;
(2) Cooling the ethyl acetate concentrated solution to below-20 ℃, controlling the temperature, slowly dripping the acidic catalyst, stirring after finishing the dripping, then slowly adding the reducing agent, stirring and preserving the temperature for reaction; after the reaction is finished, slowly dripping water, and stirring after dripping; adjusting the pH value to be alkaline, stirring, separating liquid, and separating an ethyl acetate layer; washing the ethyl acetate layer with saturated saline solution, repeating the operation once, separating the liquid, and separating the ethyl acetate layer for later use;
(3) Heating the ethyl acetate layer, dropwise adding a salt forming solution, stirring after dropwise adding, then adding methanol, continuously stirring, washing the solvent, draining the filter cake, and drying to obtain the product.
Further, in the step (1), the compound IV is (S) -5-oxopiperidine-2-carboxylic acid ethyl ester, (S) -5-oxopiperidine-2-carboxylic acid methyl ester, (S) -5-oxopiperidine-2-carboxylic acid butyl ester or (S) -5-oxopiperidine-2-carboxylic acid benzyl ester; the amino compound is O- (tetrahydro-2H-pyran-2-yl) hydroxylamine or hydrochloride, sulfate and phosphate thereof.
Further, the molar ratio of the compound IV to the amine-based compound is 1.0-2.0, preferably 1.0-1.5.
Further, in the step (1), the temperature of the temperature raising reaction is 55 to 75 ℃, and the reaction time is 2 to 6 hours, preferably 2 to 3 hours.
Further, in the step (2), the acidic catalyst is glacial acetic acid, cyanoacetic acid, hydrochloric acid, sulfuric acid, propionic acid, n-butyric acid or isobutyric acid; the molar ratio of the addition amount of the acidic catalyst to the oxime compound is 2.5; the reducing agent is sodium triacetoxyborohydride, sodium tricyano borohydride, sodium tripropacyloxy borohydride, potassium tricyano borohydride or potassium triacetoxyborohydride; the pH regulator is one or a mixture of ammonia water, ammonia gas, isopropylamine, ethylenediamine and triethylamine, and preferably ammonia water; the molar ratio of the reducing agent to the oxime compound is 2-4; the volume ratio of the ethyl acetate concentrated solution to water is 2; the pH is 8.0-9.0.
Further, in the step (2), the temperature of the heat preservation reaction is-40 to-20 ℃, preferably-30 to-20 ℃, and the reaction time is 10 to 12 hours.
Further, in the step (3), the salt forming solution is selected from one or a mixture of oxalic acid, malonic acid, succinic acid and glutaric acid, preferably oxalic acid; the molar ratio of the compound oxime to the oxalic acid solution is 1; the salifying solution is prepared by selecting a solvent from one or a mixture of isopropanol, isoamylol and isobutanol, preferably isopropanol; .
The preparation method provided by the invention has the following specific reaction formula:
Figure DEST_PATH_IMAGE003
the invention has the beneficial effects that:
(1) The invention provides a preparation method of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic ester salt, which has the advantages of short reaction steps, simple process operation, less three wastes in reaction and easiness in industrial production.
(2) The preparation method of the 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic ester salt has the advantages of wide raw material source, strong material selectivity and lower cost in the preparation process.
Detailed Description
The benefits of the present invention are further described by the following examples, which are intended to be illustrative only and should not be construed as limiting the invention, as modifications and variations apparent to those skilled in the art are intended to be within the scope of the invention.
Example 1
Weighing 50g (0.292 mol) of (S) -5-oxo piperidine-2-carboxylic acid ethyl ester and 500ml of ethyl acetate, adding the mixture into a 1000ml three-necked bottle, stirring to dissolve, adding 37.6g (1.1eq, 0.32mol) of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, then heating to 60-70 ℃ for reaction for 2-3H. The reaction was complete as detected by HPLC. After the reaction was completed, the heating was turned off, the temperature was reduced to room temperature, and the organic phase was washed with 200ml of saturated brine, followed by liquid separation. The ethyl acetate layer was separated, 25g of anhydrous sodium sulfate was added, dried for 30min, filtered, and the filtrate was concentrated to 200ml.
Cooling 200ml ethyl ester concentrated solution to below-20 ℃, controlling the temperature, slowly dropwise adding 43.5g (2.5eq, 0.725mol) of glacial acetic acid, stirring for 30min after the addition, then slowly adding 122.9g (2.0eq, 0.58mol) of sodium triacetoxyborohydride for about 1h, and stirring and preserving the temperature for reaction for 10-12 h after the addition. After the reaction is finished, slowly dropwise adding 100ml of water for quenching, and stirring for 20min after dropwise adding; adding 25% ammonia water to adjust the pH value to 8.0-9.0, stirring for 30min, separating liquid, and separating an ethyl acetate layer; the ethyl acetate layer was washed with 100ml of saturated brine and repeated, and the ethyl acetate layer was separated.
The ethyl acetate layer was transferred to a 500ml three-necked flask, the temperature was raised to 50 ℃ and 60ml of an isopropanol solution containing 40.3g (1.1eq, 0.32mol) of oxalic acid dihydrate was added dropwise over about 30min, after dropping, stirring was continued for 1h, then 60ml of methanol was added. 20ml ethyl acetate, 20ml methanol and 20ml ethyl acetate. And (4) pumping the filter cake, and drying to obtain an oxalate product. Material receiving amount: 56.3g; the yield is 61.2%; the purity was 99.51%, wherein the enantiomer was "2R,5S configuration content 0.20%".
Example 2
Weighing 50g (0.292 mol) of (S) -5-oxopiperidine-2-carboxylic acid ethyl ester and 500ml of ethyl acetate, adding the mixture into a 1000ml three-necked bottle, stirring the mixture to dissolve the mixture, adding 44.4g (1.3eq, 0.38mol) of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, heating the mixture to 60-70 ℃, and reacting the mixture for 2-3 hours. The reaction was complete as detected by HPLC. After the reaction was completed, the heating was turned off, the temperature was reduced to room temperature, and the organic phase was washed with 200ml of saturated brine, followed by liquid separation. The ethyl acetate layer was separated, 25g of anhydrous sodium sulfate was added, dried for 30min, filtered, and the filtrate was concentrated to 200ml.
Cooling 200ml ethyl ester concentrated solution to below-20 ℃, controlling the temperature, slowly dropwise adding 43.5g (2.5eq, 0.725mol) of glacial acetic acid, stirring for 30min after the addition, then slowly adding 122.9g (2.0eq, 0.58mol) of sodium triacetoxyborohydride for about 1h, and stirring and preserving the temperature for reaction for 10-12 h after the addition. After the reaction is finished, slowly dropwise adding 100ml of water for quenching, and stirring for 20min after dropwise adding; adding 25% ammonia water to adjust the pH value to 8.0-9.0, stirring for 30min, separating liquid, and separating an ethyl acetate layer; the ethyl acetate layer was washed with 100ml of saturated brine, and the operation was repeated once to separate the liquid, and the ethyl acetate layer was separated.
The ethyl acetate layer was transferred to a 500ml three-necked flask, the temperature was raised to 50 ℃ and 60ml of an isopropanol solution containing 40.3g (1.1eq, 0.32mol) of oxalic acid dihydrate was added dropwise over about 30min, after dropping, stirring was continued for 1h, then 60ml of methanol was added. 20ml ethyl acetate, 20ml methanol and 20ml ethyl acetate. And (4) pumping the filter cake, and drying to obtain an oxalate product. Material receiving amount: 56.6g; the yield is 61.5%; the purity was 99.47%, wherein the enantiomer was "2R,5S configuration content 0.22%".
Example 3
50g (0.292 mol) of (S) -5-oxo piperidine-2-carboxylic acid ethyl ester and 500ml of ethyl acetate are weighed and added into a 1000ml three-necked bottle, stirred and dissolved, 37.6g (1.1eq, 0.32mol) of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine is added, and then the temperature is raised to 60-70 ℃ for reaction for 4 hours. The reaction was complete as detected by HPLC. After the reaction was completed, the heating was turned off, the temperature was reduced to room temperature, and the organic phase was washed with 200ml of saturated brine, followed by liquid separation. The ethyl acetate layer was separated, 25g of anhydrous sodium sulfate was added, dried for 30min, filtered, and the filtrate was concentrated to 200ml.
Cooling 200ml ethyl ester concentrated solution to below-20 ℃, controlling the temperature, slowly dropwise adding 43.5g (2.5eq, 0.725mol) of glacial acetic acid, stirring for 30min after the addition, then slowly adding 122.9g (2.0eq, 0.58mol) of sodium triacetoxyborohydride for about 1h, and stirring and preserving the temperature for reaction for 10-12 h after the addition. After the reaction is finished, slowly dropwise adding 100ml of water for quenching, and stirring for 20min after the dropwise adding is finished; adding 25% ammonia water to adjust the pH value to 8.0-9.0, stirring for 30min, separating liquid, and separating out an ethyl acetate layer; the ethyl acetate layer was washed with 100ml of saturated brine, and the operation was repeated once to separate the liquid, and the ethyl acetate layer was separated.
The ethyl acetate layer was transferred to a 500ml three-necked flask, the temperature was raised to 50 ℃ and 60ml of an isopropanol solution containing 40.3g (1.1eq, 0.32mol) of oxalic acid dihydrate was added dropwise over about 30min, after dropping, stirring was continued for 1h, then 60ml of methanol was added. 20ml ethyl acetate, 20ml methanol and 20ml ethyl acetate. And (4) drying the filter cake by pumping and drying to obtain an oxalate product. Material receiving amount: 50.7g; the yield is 55.09%; the purity was 99.43%, wherein the enantiomer was "2R,5S configuration content 0.19%".
Example 4
Weighing 50g (0.292 mol) of (S) -5-oxo piperidine-2-carboxylic acid ethyl ester and 500ml of ethyl acetate, adding the mixture into a 1000ml three-necked bottle, stirring and dissolving, adding 37.6g (1.1eq, 0.32mol) of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, then heating to 60-70 ℃ for reaction for 2-3H. The reaction was complete as detected by HPLC. After the reaction was completed, the heating was turned off, the temperature was reduced to room temperature, and the organic phase was washed with 200ml of saturated brine, followed by liquid separation. The ethyl acetate layer was separated, 25g of anhydrous sodium sulfate was added, dried for 30min, filtered, and the filtrate was concentrated to 200ml.
Cooling 200ml ethyl ester concentrated solution to below-20 ℃, controlling the temperature, slowly dripping 43.5g (2.5eq, 0.725mol) of glacial acetic acid, stirring for 30min after the addition, then slowly adding 245.8g (4.0eq, 1.16mol) of sodium triacetoxyborohydride for about 1h, and stirring and preserving the temperature for reaction for 10-12 h after the addition. After the reaction is finished, slowly dropwise adding 100ml of water for quenching, and stirring for 20min after the dropwise adding is finished; adding 25% ammonia water to adjust the pH value to 8.0-9.0, stirring for 30min, separating liquid, and separating an ethyl acetate layer; the ethyl acetate layer was washed with 100ml of saturated brine, and the operation was repeated once to separate the liquid, and the ethyl acetate layer was separated.
The ethyl acetate layer was transferred to a 500ml three-necked flask, the temperature was raised to 50 ℃ and 60ml of an isopropyl alcohol solution containing 40.3g (1.1eq, 0.32mol) of oxalic acid dihydrate was added dropwise over about 30min, after dropping, stirring was continued for 1h, then 60ml of methanol was added, and stirring was continued. 20ml ethyl acetate, 20ml methanol and 20ml ethyl acetate. And (4) pumping the filter cake, and drying to obtain an oxalate product. Material receiving amount: 52.1g; the yield is 56.63%; the purity was 99.48%, wherein the enantiomer was "2R,5S configuration content 0.24%".
Example 5
Weighing 50g (0.292 mol) of (S) -5-oxo piperidine-2-carboxylic acid ethyl ester and 500ml of ethyl acetate, adding the mixture into a 1000ml three-necked bottle, stirring and dissolving, adding 37.6g (1.1eq, 0.32mol) of O- (tetrahydro-2H-pyran-2-yl) hydroxylamine, then heating to 60-70 ℃ for reaction for 2-3H. The reaction was complete as detected by HPLC. After the reaction was completed, the heating was turned off, the temperature was reduced to room temperature, and the organic phase was washed with 200ml of saturated brine, followed by liquid separation. The ethyl acetate layer was separated, 25g of anhydrous sodium sulfate was added, dried for 30min, filtered, and the filtrate was concentrated to 200ml.
Cooling 200ml ethyl ester concentrated solution to below-20 ℃, controlling the temperature, slowly dropwise adding 43.5g (2.5eq, 0.725mol) of glacial acetic acid, stirring for 30min after the addition, then slowly adding 122.9g (2.0eq, 0.58mol) of sodium triacetoxyborohydride for about 1h, and stirring and preserving the temperature for reaction for 10-12 h after the addition. After the reaction is finished, slowly dropwise adding 100ml of water for quenching, and stirring for 20min after the dropwise adding is finished; adding 25% ammonia water to adjust the pH value to 8.0-9.0, stirring for 30min, separating liquid, and separating out an ethyl acetate layer; the ethyl acetate layer was washed with 100ml of saturated brine, and the operation was repeated once to separate the liquid, and the ethyl acetate layer was separated.
The ethyl acetate layer was transferred to a 500ml three-necked flask, the temperature was raised to 50 ℃ and 60ml of an isobutanol solution containing 40.3g (1.1eq, 0.32mol) of oxalic acid dihydrate was added dropwise over about 30min, after the addition, the mixture was stirred for 1h, then 60ml of methanol was added, and the stirring was continued. 20ml ethyl acetate, 20ml methanol and 20ml ethyl acetate. And (4) drying the filter cake by pumping and drying to obtain an oxalate product. Material receiving amount: 55.8g; the yield is 60.7%; purity was 99.54%, with enantiomer "2r,5s configuration content 0.28%".
Comparative example 1
50g (0.292 mol) of (S) -5-oxopiperidine-2-carboxylic acid ethyl ester and 500ml of ethyl acetate are weighed, added into a 1000ml three-necked bottle, stirred and dissolved, 51.1g (1.1eq, 0.32mol) of benzyloxyammonia hydrochloride is added, then the temperature is raised to 60-70 ℃ for reaction, and the reaction time is 2-3 h. The reaction was complete as detected by HPLC. After the reaction was completed, the heating was turned off, the temperature was reduced to room temperature, and the organic phase was washed with 200ml of saturated brine, followed by liquid separation. The ethyl acetate layer was separated, 25g of anhydrous sodium sulfate was added, dried for 30min, filtered, and the filtrate was concentrated to 200ml.
Cooling 200ml ethyl ester concentrated solution to below-20 ℃, controlling the temperature, slowly dropwise adding 43.5g (2.5eq, 0.725mol) of glacial acetic acid, stirring for 30min after the addition, then slowly adding 122.9g (2.0eq, 0.58mol) of sodium triacetoxyborohydride for about 1h, and stirring and preserving the temperature for reaction for 10-12 h after the addition. After the reaction is finished, slowly dropwise adding 100ml of water for quenching, and stirring for 20min after dropwise adding; adding 25% ammonia water to adjust the pH value to 8.0-9.0, stirring for 30min, separating liquid, and separating an ethyl acetate layer; the ethyl acetate layer was washed with 100ml of saturated brine, and the operation was repeated once to separate the liquid, and the ethyl acetate layer was separated.
The ethyl acetate layer was transferred to a 500ml three-necked flask, the temperature was raised to 50 ℃ and 60ml of an isopropanol solution containing 40.3g (1.1eq, 0.32mol) of oxalic acid dihydrate was added dropwise over about 30min, after dropping, stirring was continued for 1h, then 60ml of methanol was added. 20ml ethyl acetate, 20ml methanol and 20ml ethyl acetate. And (4) pumping the filter cake, and drying to obtain an oxalate product. Material receiving amount: 56.3g; the yield is 61.2%; the purity was 99.0%, wherein the enantiomer was "2R,5S configuration content 60.3%".

Claims (8)

1. A process for the preparation of a 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ester salt comprising the steps of:
(1) Adding ethyl acetate into (S) -5-oxo piperidine-2-carboxylic ester, mixing, stirring and dissolving, adding an amino compound for reaction, and then heating for reaction; after the reaction is finished, cooling to room temperature, washing an organic phase by using saturated saline solution, and then separating liquid; separating ethyl acetate layer, adding anhydrous sodium sulfate, drying, filtering, concentrating the filtrate to 0.4 times of original volume to obtain ethyl acetate concentrated solution of oxime compound;
(2) Cooling the ethyl acetate concentrated solution to below-20 ℃, controlling the temperature, slowly dropwise adding an acidic catalyst, stirring after adding, then slowly adding a reducing agent, and stirring and preserving heat for reaction after adding; after the reaction is finished, slowly dripping water, and stirring after dripping; adjusting the pH value to be alkaline, stirring, separating liquid, and separating an ethyl acetate layer; washing the ethyl acetate layer with saturated saline solution, repeating the operation once, separating the liquid, and separating the ethyl acetate layer for later use;
(3) Heating the ethyl acetate layer, dropwise adding a salt forming solution, stirring after the dripping, then adding methanol, continuously stirring, washing the solvent, pumping out the filter cake, and drying to obtain the product.
2. The process according to claim 1, wherein in the step (1), the (S) -5-oxopiperidine-2-carboxylic acid ester is ethyl (S) -5-oxopiperidine-2-carboxylate, methyl (S) -5-oxopiperidine-2-carboxylate, butyl (S) -5-oxopiperidine-2-carboxylate or benzyl (S) -5-oxopiperidine-2-carboxylate; the amino compound is O- (tetrahydro-2H-pyran-2-yl) hydroxylamine or hydrochloride, sulfate and phosphate thereof.
3. The process according to claim 1 or 2, wherein the molar ratio of the (S) -5-oxopiperidine-2-carboxylic acid ester to the amine-based compound is 1.0 to 2.0, preferably 1.0 to 1.5.
4. The process according to claim 1, wherein the temperature of the temperature-increasing reaction in step (1) is 55 to 75 ℃ and the reaction time is 2 to 6 hours, preferably 2 to 3 hours.
5. The method according to claim 1, wherein in the step (2), the acidic catalyst is glacial acetic acid, cyanoacetic acid, hydrochloric acid, sulfuric acid, propionic acid, n-butyric acid or isobutyric acid; the molar ratio of the added amount of the acidic catalyst to the oxime compound is 2.5; the reducing agent is sodium triacetoxyborohydride, sodium tricyano borohydride, sodium tripropacyloxy borohydride, potassium tricyano borohydride or potassium triacetoxyborohydride; the pH regulator is one or a mixture of ammonia water, ammonia gas, isopropylamine, ethylenediamine and triethylamine, and preferably ammonia water; the molar ratio of the reducing agent to the oxime compound is 2-4; the volume ratio of the ethyl acetate concentrated solution to water is 2; the pH is 8.0-9.0.
6. The process according to claim 1 or 5, wherein the temperature of the incubation reaction in step (2) is-40 to-20 ℃, preferably-30 to-20 ℃, and the reaction time is 10 to 12 hours.
7. The preparation method according to claim 1, characterized in that, in the step (3), the salt forming solution is selected from one or a mixture of oxalic acid, malonic acid, succinic acid and glutaric acid, preferably from oxalic acid; the molar ratio of the compound oxime to the oxalic acid solution is 1.
8. The method according to claim 7, wherein in the step (3), the solvent of the salt-forming solution is selected from one or a mixture of isopropanol, isoamyl alcohol and isobutanol, preferably isopropanol.
CN202210778032.9A 2022-07-04 2022-07-04 Process for the preparation of 5R- (((tetrahydro-2H-pyran-2-yl) oxy) amino) piperidine-2S-carboxylic acid ester salts Pending CN115232113A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015097071A1 (en) * 2013-12-25 2015-07-02 Syngenta Participations Ag Herbicidal haloalkylsulphonamide derivatives
CN107540601A (en) * 2016-06-28 2018-01-05 新发药业有限公司 The convenient preparation method of 5R benzyloxies amino piperidine 2S formic acid esters and its oxalates
US20190152953A1 (en) * 2015-08-06 2019-05-23 Ube Industries, Ltd. Substituted guanidine derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015097071A1 (en) * 2013-12-25 2015-07-02 Syngenta Participations Ag Herbicidal haloalkylsulphonamide derivatives
US20190152953A1 (en) * 2015-08-06 2019-05-23 Ube Industries, Ltd. Substituted guanidine derivatives
CN107540601A (en) * 2016-06-28 2018-01-05 新发药业有限公司 The convenient preparation method of 5R benzyloxies amino piperidine 2S formic acid esters and its oxalates

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