A preparation method of a high-optical-purity chiral oxo-aza-cycloalkane compound comprises the steps of: (R or S)N-substituent P-2-alkoxycarbonylalkyliminodiacetic acid diester as the raw material is cyclized in the presence of a solvent and a cyclization reagent (lewis acid-lewis base) to obtain high-optical-purity N-substituent P -2- (R or S)- substituent G oxo-aza-cycloalkane or the salt thereof through thermal decarboxylation or hydrolysis decarboxylation reaction; the specific type of cyclization reagent used in the present invention is conductive to the preparation of the high-optical-purity target product, easily recoverable, with reduced waste liquid discharge, green, and environment-friendly, which contributes to green industrial production.
C07D 211/60 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
C07D 207/16 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
2.
ENVIRONMENTALLY FRIENDLY PREPARATION METHOD FOR SUBSTITUTED ISONITRILE COMPOUND
66. The present invention can be carried out by using a continuous flow means, thus improving production efficiency, and reducing operation. In the present invention, a byproduct of trisubstituted phosphine oxide is generated in the reaction process and may be recycled, and costs are reduced; in the present invention, phosphorus oxychloride and phosphorus pentoxide which are expensive and which generate a large amount of wastewater during the preparation process are not used as dehydrating agents, and a high-temperature dehydration reaction is also not needed; in addition, the process and operation are easy and convenient, phosphorus-containing wastewater is not discharged during the process, and the method is environmentally friendly and has low costs. The method has high atom economy, high target product yield and purity, and is suitable for industrial application.
Disclosed is an environmentally friendly preparation method for a substituted oxazole compound, said method uses an N-substituted formyl-α-substituted glycinate as a starting material, and a substituted oxazole compound is obtained under the action of an organic amine and a dehydrating agent such as a tri-substituted phosphine dihalide, a combination of a tri-substituted phosphine dihalide and an acyl halide reagent, or a combination of a tri-substituted phosphine oxide and an acyl halide reagent, and upon undergoing a cyclization reaction. The resulting substituted oxazole compound can further undergo saponification and decarboxylation to obtain a pharmaceutical intermediate 4-substituted-5-substituted oxyoxazole. The method can be performed in a continuous flow manner, improving production efficiency and reducing operations; and a tri-substituted phosphine oxide biproduct can be recycled, lowering costs. The present method does not phosphorous oxychloride and phosphorus pentoxide, which are expensive and have a preparation process that produces a large amount of wastewater, to serve as dehydrating agents, and a high temperature cyclization reaction is unneeded; the present invention has a simple process, operation is simple and convenient, no phosphorous-containing wastewater is discharged during the process, the present invention is environmentally friendly and low-cost, has high atom economy, has high yield and purity for a target product, and is suitable for industrialized application.
A simple method is preparing Vaborbactam, in which S-3-hydroxy-6-oxohexanoic acid ester is used as the starting material to finally form the Vaborbactam (I) by carrying out the procedures of hydroxyl protection, imidization, asymmetric addition from borane or borate compounds, amino deprotection, amidation, cyclization and hydrolysis. The present invention is suitable for commercial production by virtue of the advantages: widely available and low cost raw materials; safe, simple and convenient process steps; no rigorous reaction conditions; and environment-friendly reaction courses.
B01J 31/28 - Catalyseurs contenant des hydrures, des complexes de coordination ou des composés organiques contenant en outre des composés métalliques inorganiques non prévus dans les groupes du groupe du platine, du cuivre ou du groupe du fer
The present invention provides a simple process of preparing avibactam. Piperidine-5-one-2S-carboxylate II as the raw material is subjected to condensation reaction with O-protecting hydroxylamine hydrochloride; the resulting compound is subjected to reduction and chiral resolution to obtain 5R-substituted oxyaminopiperidine-2S-carboxylic acid V in a basic condition; then, the compound of formula V is subjected to urea cyclization, acyl chlorination, and amidation with phosgene, solid phosgene, or diphosgene in a “one-pot” process, and then subjected to deprotection, sulfation, and tetrabutylammonium salt formation reaction to obtain (2S,5R)-2-carbamoyl-7-oxo-1,6-diazabicyclo[3.2.1]octan-6-yl]oxy}sulfonyl tetra-n-butyl ammonium salt VII, and finally, the compound of formula VII is subjected to ion exchange to obtain avibactam I.
The present application relates to methods of preparing 5R-[(benzyloxy) amino] piperidine-2S-carboxylic acid or its derivatives in an environment-friendly way. The method uses L-glutamic acid as a starting material, which is first subjected to esterification reaction in the presence of an acidic reagent, and then reacted successively with 2-haloacetate and N-protecting agent, or with N-protecting agent and 2-haloacetate under a basic condition to obtain compound IV; then, the obtained compound IV is subjected to intramolecular condensation into a ring under the action of a strong base to obtain N-protecting group piperidine-5-one-2S-carboxylate (V).
C07D 211/60 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
C07D 211/02 - Préparation par cyclisation ou hydrogénation
7.
PREPARATION METHOD FOR CHIRAL OXOAZACYCLOALKANE COMPOUND HAVING HIGH OPTICAL PURITY
A preparation method for a chiral oxoazacycloalkane compound as shown in formula (I), comprising the steps of: using a compound as shown in formula (II) of R or S as a raw material, performing a cyclization reaction under the action of a solvent and a cyclization reagent, i.e. a Lewis acid-Lewis base, and then performing a thermal decarboxylation or a hydrolysis decarboxylation reaction. The raw material and product involved in the preparation method have a good chiral structure stability, and the target product has high optical purity and yield.
C07D 211/60 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
C07D 207/16 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
C07D 223/06 - Composés hétérocycliques contenant des cycles à sept chaînons ne comportant qu'un atome d'azote comme unique hétéro-atome du cycle non condensés avec d'autres cycles avec des hétéro-atomes ou avec des atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile, liés directement aux atomes de carbone du cycle
A method for preparing 3-hydroxy-6-oxohexanoate. In the method, haloacetaldehyde acetal is used as the starting material, and is subjected to Grignardation and nucleophilic substitution reaction to obtain key epoxide intermediates; then a target product is obtained by metal-catalyzed carburization reaction in carbon monoxide, or a target product is obtained by means of a carburization reaction carried out using a cyanide, hydrolysis of the cyano group and an acetal, and esterification. The obtained target product is used in preparation of Vaborbactam and isomers thereof. The method uses raw materials which are cheap and easy to obtain, has reaction conditions which are mild and easy to control and a simple and safe process, is environment-friendly and low in costs, and can implement green industrial production.
C07C 69/732 - Esters d'acides carboxyliques dont le groupe carboxyle estérifié est lié à un atome de carbone acyclique et dont l'un des groupes OH, O-métal, —CHO, céto, éther, acyloxy, des groupes , des groupes ou des groupes se trouve dans la partie acide d'acides non saturés d'acides hydroxycarboxyliques non saturés
C07C 47/263 - Composés non saturés comportant des groupes —CHO liés à des atomes de carbone acycliques contenant des groupes hydroxyle acycliques
A simple preparation method for vaborbactam: using S-3-hydroxy-6-oxohexanoate as a starting raw material, performing hydroxyl protection, imidization, asymmetric addition of borane or borate compounds, deamination of protecting groups, amidation, and cyclisation hydrolysis to prepare vaborbactam. The present method uses cheap and readily available raw materials, is low-cost, has safe and easy processing procedures, does not require harsh reaction conditions, has an environmentally friendly reaction process, and is suitable for industrial production.
Provided in the present invention is a preparation method for (S)-glycidyl phthalimide (II). Phthalimide (III) and (S)-1-substituent propylene oxide (IV) are used as raw materials, a reaction occurs under the action of a catalyst to generate 2-((S)-3-substituent-2-hydroxypropyl isodihydroindole-1,3-dione (V), and finally (S)-glycidyl phthalimide (II) is generated by means of a ring-closure reaction. The method of the present invention uses cheap and easy-to-obtain raw materials, has easy reaction conditions, and is low cost; moreover, the reaction route is short, operation is easy and post-processing is simple. In addition, the method has fewer side reactions, a high target product yield and purity, and is suitable for industrial production.
C07D 405/06 - Composés hétérocycliques contenant à la fois un ou plusieurs hétérocycles comportant des atomes d'oxygène comme uniques hétéro-atomes du cycle et un ou plusieurs hétérocycles comportant des atomes d'azote comme uniques hétéro-atomes du cycle contenant deux hétérocycles liés par une chaîne carbonée contenant uniquement des atomes de carbone aliphatiques
C07D 413/14 - Composés hétérocycliques contenant plusieurs hétérocycles, au moins un cycle comportant des atomes d'azote et d'oxygène comme uniques hétéro-atomes du cycle contenant au moins trois hétérocycles
11.
PREPARATION METHOD FOR 4-(4-AMINOPHENYL)MORPHOLIN-3-ONE
The present invention relates to a preparation method for 4-(4-aminophenyl) morpholin-3-one. Said method comprises: using p-nitroaniline as a raw material, successively performing an amidation reaction and a catalytic hydrogenation reaction to obtain a p-acyl-substituted aminophenylamin, and then sequentially performing an amidation reaction, a halogenation reaction or a sulfonylation reaction with 1,4-dioxane-2-one to prepare N-(2-substituted ethyloxyacetyl) p-acyl-substituted aminophenylamin, performing a condensation cyclization reaction under the action of a base to obtain 4-(4-substituted acylaminophenyl) morpholin-3-one, and finally removing an acyl protecting group, so as to obtain a target product. The raw materials used in the present invention are cheap and easy to obtain. The method of the present invention is easy to operate, and has low cost. The reactions involved in each step have high activity and specificity, and are easy to carry out, and the products have high purity and high yield.
C07D 265/32 - Oxazines-1, 4Oxazines-1, 4 hydrogénées non condensées avec d'autres cycles avec des atomes d'oxygène liés directement aux atomes de carbone du cycle
C07C 235/16 - Amides d'acides carboxyliques, le squelette carboné de la partie acide étant substitué de plus par des atomes d'oxygène ayant des atomes de carbone de groupes carboxamide liés à des atomes de carbone acycliques et des atomes d'oxygène, liés par des liaisons simples, liés au même squelette carboné le squelette carboné étant acyclique et saturé ayant l'atome d'azote d'au moins un des groupes carboxamide lié à un atome de carbone d'un cycle aromatique à six chaînons
C07C 231/02 - Préparation d'amides d'acides carboxyliques à partir d'acides carboxyliques ou à partir de leurs esters, anhydrides ou halogénures par réaction avec de l'ammoniac ou des amines
12.
METHOD FOR PREPARING 5R-BENZYLOXYAMINOPIPERIDIN-2S-CARBOXYLIC ACID OR DERIVATIVE THEREOF
The present invention relates to a green method for preparing 5R-benzyloxyaminopiperidin-2S-carboxylic acid or derivatives thereof. According to the method, L-glutamic acid, used as a starting raw material, is subjected to esterification in the presence of an acidic reagent, and is then successively reacted with 2-haloacetate and an N-protective reagent, or the N-protective reagent and the 2-haloacetate under alkaline conditions to obtain a compound IV, wherein same is then subjected to ring formation by intramolecular condensation under the action of strong base to obtain an N-protective group piperidin-5-one-2S-carboxylate (V). The resulting compound V is sujected to one of the following routes for preparing the 5R-benzyloxyaminopiperidin-2S-carboxylic acid (or carboxylate): route 1: the compound V is subjected to protective group-removing, condensation with a benzyloxy ammonia hydrochloride, imine-reduction-chiral resolution, neutralization, and hydrolysis; route 2: hydrolysis of the compound V, protective group removing, condensation of benzyloxy ammonia hydrochloride, reduction-chiral resolution of imine, and neutralization; and route 3: the compound V is subjected to condensation with benzyloxy ammonia hydrochloride, imine-reduction-chiral resolution, protective group-removing, neutralization, and hydrolysis. This route can be achieved by a "one pot method".
C07D 211/02 - Préparation par cyclisation ou hydrogénation
C07D 211/60 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
C07D 211/68 - Composés hétérocycliques contenant des cycles pyridiques hydrogénés, non condensés avec d'autres cycles avec uniquement des atomes d'hydrogène et de carbone liés directement à l'atome d'azote du cycle comportant une liaison double entre chaînons cycliques ou entre chaînon cyclique et chaînon non cyclique
C07B 57/00 - Séparation de composés organiques optiquement actifs
Provided is a preparation method for Avibactam, comprising using piperidin-5-one-2S-formate II as a raw material, subjecting same to a condensation reaction with O-protective group hydroxylamine hydrochloride, then performing reduction, chiral separation and hydrolysis under alkaline conditions to obtain 5R-substitutent oxyaminopiperidine-2S-formic acid V; and then subjecting the compound to a cyclic urea forming reaction and a chloroformylation reaction with phosgene, triphosgene or diphosgene, and performing amidation, deprotection, sulphation, and tetrabutylammonium amminiation to form a salt {[(2S,5R)-2-carbamoyl-7-oxo-1,6-diazacyclo[3.2.1]octane-6-yl]oxy}sulfonyltetra-n-butylammonium VII, and finally obtaining Avibactam I by means of ion exchange. The preparation method is simple, is easy to operate, has low raw material price, has low cost, has small amounts of "three wastes" emission, has high atomic utilization rate, is economical and environmentally friendly, and has high yield in each step, being beneficial to the industrial production of Avibactam.
C07D 211/60 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
The present invention discloses a simple preparation method for an Avibactam intermediate. The present invention uses a compound of formula III as a raw material, hydrolyzes the compound under alkaline conditions, acidifies the resultant product to prepare a compound of formula IV, and subjects the obtained compound of formula IV to simultaneous cyclocarbamide forming and chlorination reactions with solid phosgene or diphosgene in the presence of an organic base and a catalyst to obtain a compound of formula V, followed by amidation to obtain a final product (II). The cyclocarbamide forming, chlorination, and amidation reactions of the present invention are carried out in a "one-pot process", meaning intermediate products do not need to be separated or purified. The present invention uses easily available raw materials, involves a simple process, has strong operability, requires no special protective agent and carbonylation reagent, has high atomic economy, low cost, and a green production process, produces the product (II) with high purity and high yield, and facilitates cost reduction and green production of Avibactam (I).
SRRSS-formate oxalate (III) as a raw material for amidation with an amide of formula IV to prepare a compound of formula V, and subjects the resultant compound V to a cyclocarbamide forming reaction with a carbonylation reagent to obtain a compound of formula VI, followed by catalytic hydrogenolysis for removal or substitution of benzyl, sulfation with a sulfur trioxide complex, and salification with tetrabutylammonium to give a final product (II). The method of the present invention features easily achievable reaction conditions, strong operability, a simple process, low cost, few by-products, and high atom economy in the reaction, and the product (II) has a high purity and high yield.
C07D 211/60 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
16.
GREEN PREPARATION METHOD FOR N-SUBSTITUTED-L-PYROGLUTAMIC ACID ESTER
The present invention provides a green preparation method for N-substituted-L-pyroglutamic acid ester (I), comprising: using L-glutamic acid (II) as a starting material, and preparing L-glutamic acid diester hydrochloride (III) by means of an esterification reaction in the presence of an acidic reagent; and then subjecting L-glutamic acid diester hydrochloride (III) to N-substituted protective reaction with an N-substituent protective reagent by means of a one-pot method in the presence of a base and a solvent, introducing an N-substituted protective group, and heating is performed for dealcoholization cyclization in molecules to obtain N-substituted-L-pyroglutamic acid ester (I). The present invention has the advantages of cheap and easily available raw materials, classic reaction types, short process route, simple and convenient operation, small amount of waste water, green and environment-friendly production process, high reaction yield, and low product costs. 5R-benzyloxyaminopiperidine-2S-formate, 5R-benzyloxyaminopiperidine-2S-carboxylate oxalate, and avibactam can be prepared from N-substituted-L-pyroglutamic acid ester (I) prepared in the present invention.
RSLLR-SRSRSRSS-formate oxalate is useful in the preparation of avibactam. The present invention uses cheap and easily available raw materials, has high reaction selectivity, and has an environmentally-friendly production process.
C07D 211/60 - Atomes de carbone comportant trois liaisons à des hétéro-atomes, avec au plus une liaison à un halogène, p. ex. radicaux ester ou nitrile
05 - Produits pharmaceutiques, vétérinaires et hygièniques
Produits et services
Vitamin preparations; drugs for medical purposes; crude
drug; dietetic substances adapted for medical use;
nutritional supplements; veterinary preparations; medicines
for veterinary purposes; dietary supplements for animals.
A Bacillus subtilis strain and uses thereof are provided, and the Bacillus subtilis strain is deposited in China Center for Type Culture Collection as CGMCC No.4018. The said Bacillus subtilis strain is obtained by ultraviolet mutagenesis, preliminary screening, second screening and verifying by small tank fermentation. The experiments show that the said Bacillus subtilis strain CGMCC No.4018 enables fermentation production of vitamin B2 with high yield, less glucose consumption and hence can be used for industrial production of vitamin B2. And the said Bacillus subtilis strain CGMCC No.4018 is favorable to improve productive efficiency and reduce production cost.
05 - Produits pharmaceutiques, vétérinaires et hygièniques
Produits et services
(1) Medicines for veterinary purposes, namely, repellents for dogs, cattle washes; additives to fodder for medical purposes, namely, animal feed additive for use as a nutritional supplement for medical purposes, enzymes for use in animal feeds to assist in digestion.
