TW565563B - Process for the production of rosettes or agglomerates of 7-ACA and for the isolation of 7-ACA by precipitation - Google Patents

Abstract

A process in the isolation of 7-aminocephalosporanic acid (7-ACA) from an alkaline, neutral or slightly acidic medium in the presence of an additive, e.g. selected from the group comprising organic carboxylic acid esters, polymeric glycols, polyacryls, amines and polyamines, melamin-formaldehyde resins or amino acids and esters thereof to obtain 7-ACA agglomerates and/or rosettes.

Description

565563 Printed by A7 B7, a member of the Central Standards Bureau of the Ministry of Distillation, π Consumer Cooperative. 5. Description of the invention (1) The present invention relates to 7-amino-cephalosporanic acid (7_Α (: α; 7_ aminocephalosporanic acid) Η Η ~ · COOH 0 7-ACA is an important intermediate compound in the synthesis of many semi-synthetic cephalosporin antibiotics. It can, for example, be prepared from cephalosporin C via the amidine function of the 7th position of the cleavage ring system-for example, Chemically, for example, in a strong acid medium, for example, by converting the amidine function to a gasified amidine function, which may be hydrolyzed to produce 7_ACA, and for example by adjusting the pH (near the isoelectric point), for example 7-ACA can be precipitated by adding alkali; 7-ACA can be isolated in the form of rosettes and aggregates;-or enzymatically, for example, through the action of hydratase; or by converting cephalosporin C into Glutaramyl · Aminocephalosporin acid, for example, 7-ACA by enzymatic hydrolysis of glutaryl-7-aminocephalosporin acid through the action of D-amino acid oxidase, for example, in alkali In neutral, neutral or slightly acidic media, The ion-exchanger or adsorbent resin purifies the reaction solution, and for example, 7-ACA is precipitated by adjusting the pH (near the isoelectric point), for example, by adding an acid, such as HC1. However, in this case, Shen Dian's 7 -ACA may be in the form of very small, loose, needle-like crystals, and it is difficult to separate. Increasing the purity of 7-ACA will result in even smaller crystal paper sizes. Applicable to China National Standard (CNS) A4 specifications (210χ 297 cm) ) --- r ----- oh ------ IX ------ ·-. (Please read the notes on the back before filling out this page.) Printed by the cooperative 565563 V. Description of the invention (In addition, before the 7-ACA is separated, an organic solvent, such as a lower alcohol, such as methanol, or a ketone, such as acetone, can be added to the reaction mixture to improve the yield. Small crystals. The present invention provides a method that can be performed, for example, on a technical scale, in which agglomerates or rosettes of 7-ACA can be formed when ACA is precipitated from a basic, neutral or slightly acidic medium, which Substantially improve 7-ACA, for example, separation by filtration and centrifugation, In addition, the ACA prepared according to the present invention can be dried more quickly, for example, it can produce a smaller amount of by-products than the 7-AC A prepared according to the prior art method. In one aspect of the present invention In this way, it provides a method for manufacturing, for example, the rosette or agglomerates of 7-ACA of formula I, characterized in that 7-ACA is in the presence of, for example, an additive selected from the group consisting of compounds defined below, Precipitates from alkaline, neutral or slightly acidic media. The additives according to the invention can be compounds which, when added in the 7_ACA precipitation method, can cause the formation of aggregates and / or rosettes, which include 'for example, the chemical formula Organic carboxylic acid esters

Ri-COO-R2 π, for example, a polymeric diol of formula III, for example, polyethylene glycol and polypropylene glycol HO- (CHR1-CHR2) k.〇H ΙΠ, for example, a polypropylene fluorenyl group of formula IV, for example Cationic, anionic, or non-ionic polypropylene fluorenyl groups, including, for example, polypropylene fluoramide,-[CHR1-CR2 (COXR3)] n- iv, -5- This paper standard applies to China National Standards ( CNS) Λ4 specification (21 OX 297 mm)-, (Please read the precautions on the back before filling this page)

565563 A7 B7 i. Description of the invention (3 For example, amines and polyamines of the following chemical formula;-[CH2-CHR6-CH2-N + RiR2.] N. R2R4N- (CH2-CH2X) n-R5 V a Vb Vc

(Please read the precautions on the back before filling this page) -Φ. For example, melamine formaldehyde resin of chemical formula VII

R7b \ / R7 N

ch5 R7a p 7a \ / 7

11 Consumers' cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs

VIII which has, for example, a molecular weight of 1,000,000, for example, 500,000, and for example, amino acids and their esters of formula VIII

RiO-CH- (NR2R4) -COOR] includes, for example, a mixture of individual additives as described above. The additives may be amino acids and their esters, which are, for example, amino acids such as lysine, for example. In the chemical formulae II, III, IV, Va, Vb, Vc, Via, VIb, VII and VIII, -6-This paper size applies to China National Standard (CNS) A4 (210X297 mm) 565563

V. Description of the invention (1, R2, R4, and R5 represent hydrogen, alkyl, or aryl, respectively; k represents an integer from 2 to 200; X represents -0- or -NRi-; R3 has Ril sufficient meaning 'or chemical formula _ (CR2R4) The group Z of m_z represents tf 'for example' an amine group, a sulfonyl group or a carboxylic acid group of the following chemical formula® / R2 ~ N \ —N \ R4 ~ S〇3H —s〇3 ° -COOH or- COO〇R4 R5, m represents an integer from 0 to 6; η represents an integer from 2 to 200,000; R6 represents hydrogen or a light group; R7a, R7b, R7c, R7d, and ft% represent hydrogen, _Ch2〇H, respectively; or the chemical formula is as follows Group ϋϋ · ϋϋ ϋϋ ϋϋ ϋϋ ϋ m ί— a ^ —Μβ —ϋ ϋϋ TJ 1 * (Please read the notes on the back before filling this page) 7b \ /

According to the policy of the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Didi, and R H) represents a group of hydrogen, alkyl, aryl, or chemical formula CH2) m-X-R5. As not specifically defined herein, alkyl includes, for example, (ci 22) alkyl, such as (Cu) alkyl, for example, lower alkyl, such as (Cl 4) alkyl, and aryl includes, for example, phenyl, Amidino, such as phenyl. This paper size applies to Chinese national standard ([~ 5) 6.4 specifications (210 '/ 297 mm) 5 565563 A7 B7 5. Description of the invention (alkyl and aryl groups include unsubstituted alkyl and aryl groups, and It will not cause alkyl and aryl groups substituted with groups other than 7-AC A to form compounds other than 7-AC A in the alkaline, neutral and slightly acidic medium under the conditions of 7-ACA; , Will not react with 7-ACA to form another compound. Alkyl includes a lower alkyl group; aryl includes phenyl, and substituted aryl includes substituted aryl, such as by Or an alkyl group substituted by a phenyl group, such as a lower alkyl group. The amino group includes an unsubstituted amino group or an ammonium group and a substituted amino group and an ammonium group, which are, for example, substituted with an alkyl group. In one aspect, it provides a method for separation from a slightly acidic, neutral, or test solution, for example, 7-ACA of Chemical Formula I, characterized in that 7-AC A is, for example, in a slightly acidic, neutral The amount in the test solution is, for example, 1 ppm to 10% selected from the group consisting of, for example, in the presence of the additives defined previously The method of the present invention can be carried out as follows: 7_ACA can be from a slightly acidic, neutral or alkaline solution of 7-ACA, which includes, for example, adding an acid to a solution of 7-ACA in a solvent to make 7-ACA Precipitation therefrom is, for example, a 7-ACA falling solution having a pΗ higher than the isoelectric point of 7-ACA in a solvent; it is relative to a strongly acidic solution in which a base is added to 7_aca to make 7-ACA Precipitation therefrom is, for example, a solution of 7-aca having a pH lower than the isoelectric point of 7-ACA in a solvent in the presence of an additive such as, for example, selected from the group including the definitions above, such as 纟 7- In the presence of the seed of ACA, it is, for example, in the form of roses and / or agglomerates (please read the precautions on the back before filling out this page) -Φ. Order printed by the Employees' Cooperatives of the Bureau of Decision and Standards of the Ministry of Economy-8 -565563 Staff Cooperative Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs of the People's Republic of China. 5. Description of the invention (6 Sinking by adding acid. The additive according to the invention is known ^, it is a known material, or it can be similar to known, For example, the known method is Jian Yu Yu. 7. · ACA is slightly acidic, neutral, or experimental The solution can be prepared, for example, using the meanings of the above commands M, A < Enzyme method. 7-ACA is not important in micro-, neutral, or test solutions. The morning is not important, and it can vary considerably. Range, including: 1. For example, about 5 to 6 grams per liter of a fan garden, such as 10 to 50 grams per liter. Additives can be, for example, before the addition of acid, or at the same time as the acid Added to 7-AC AA moved to ω · 丄 丨 · A in slightly I, neutral or alkaline solution. Additives according to the present invention flea τ deheating: weight is not important, for example, based on ecology The reason is that a low amount of the additive, for example, the amount of the 7-ACA solution is about 1 to ^ (Wv) may be appropriate. In the case of using a non-polymeric additive such as, for example, organic vinegar as an additive, for example, an amount of about 1% to 1 ()% may be appropriately 'in the case of using 1, amino acid or an ester thereof, for example, about 0.01 / ❶ to 10%, such as, for example, an amount of about 0.005% to 5% may be appropriate; in the case of using a polymerizing additive, for example, such as polypropylene polyamine, polymerized glycol, such as' About 1 to loo PPm may be appropriate. For example, the 7-ACA seed crystal as defined above can be added to the 7-ACA solution or the resulting crystal suspension before or simultaneously with the acid. The method of the present invention can be carried out in a batch or continuous manner over a wide temperature range and includes, for example, 45. To 4 0, such as 0. 2 5. (:. Suitable acids include inorganic acids, for example, sulfuric acid, hydrochloric acid, or phosphoric acid, organic acids, such as acetic acid. The acid is sufficient to make 7-ACA, for example, in a high yield, the degree of precipitation from the solution to or out of-- ! (Please read the precautions on the back before filling this page) Order • 9- This paper size is applicable to Chinese National Standard (CNS) A4 (210X 297 mm) Printed by the Ministry of Standards Bureau's Consumer Cooperatives 565563 A7- ---_ B7___ V. Description of the invention (7)-Added in t. The reaction mixture of 7-ACA in the vicinity of the isoelectric point in the solvent can be easily formed, including, but not limited to, 25 to 6卩 11, such as 3 · 5 to 5 · 5. 7-ACA can be added when the acid is added, for example, in the form of crystals. The resulting crystal suspension can be adjusted, for example, near the isoelectric point, for example, during cooling. The 7-AC A obtained, for example, in a crystalline form and in an agglomerate and / or rosette form can be obtained, for example, in a conventional manner, such as by filtration, centrifugation, washing and drying as needed, and Precipitate and separate. Drying temperature can be low temperature. 40 ° to 50 °, for example under air, and the drying time may not be long, for example about 5 to 30, such as 10 to 20 hours. The presence of the additive according to the invention in the precipitation of 7-ACA can surprisingly lead Formation of agglomerates or rosettes of 7-ACA, even in the presence of organic solvents such as alcohols or ketones in solution, and even if, for example, purification via absorbent resins, such as with Amberlite XAD 1600R > XE-714r > Dianion HP21R > Sepabeads SP825R > SP850R 'or in the case of high purity 7-ACA obtained by purification with an ion exchanger, for example using IRA 42〇r. 7-ACA crystal suspension obtained according to the present invention The filtration time in the presence of additives can be greatly reduced compared to the filtration time of 7-ACA obtained without the additives, for example from about 15 minutes to 1 minute and even lower, such as about 0.4 minutes. The following implementation The examples are used to illustrate the present invention. The temperature is expressed in degrees Celsius and is uncorrected. 7-AC A is, for example, the 7 amino cephalosporin acid of Chemical Formula I. Examples 1 to 14-General Procedures-This paper scale Applicable to China National Standard (CNS) A4 specification (210X297 mm) (Please read the precautions on the back before filling out this page) • Lu ·, 11 565563 A7 _________ ^ B7_____ V. Description of the invention (8) A ^ — will be 142 ml Water and 2.2 g of 7_ACA in the form of rosette and / or agglomerates as seeding materials were placed in a precipitation reactor, and the pH was adjusted to 5.5 using m NaOH. 25 grams of 7_ACA, 708 halo water in the form of a sodium salt, with or without a solution of about 7.0 pH with the methanol (in milliliters) described in Table 1 below, and the additives described in Table 1 below, and The resulting mixture was added dropwise to the mixture in the reactor at about 18 minutes with stirring over a period of about 25 minutes. During the process of adding the 7-ACA mixture to the mixture in the Shendian reactor, the pH of the resulting reaction mixture was adjusted to 5.5 by adding 20% sulfuric acid. The pH of the obtained suspension was adjusted to 4.0, and the suspension was cooled to 0. And stir for about 1 hour. The obtained crystal 7-ACA was decanted, washed with 120 l of water, and 200 ml of 70% methanol and 120 ml of methanol were mixed at about 50. It was dried in the air (about mbar) for about 16 hours. The filtering time (in minutes) is summarized in Table 1 below. (Please read the notes on the back before filling this page)

, 1T Seal of Consumer Cooperatives of Employees of the Central Standards Bureau of the Ministry of Economic Affairs • I--I _ = This paper size applies to China National Standard (CNS) A4 specifications (210X297 mm), which is about the date of application ^ L, β, > No. 87108573 Category OcrjD (The above are all noted by the Bureau) Α4 The name of the invention is Peiyi ;; 1 Supplement .t 丨, _r '" ——. ~; (Amended in May 1990) Returned Patent Specification 565563 Chinese Method of manufacturing 7-ACA rose flower or agglomerate and method of separating and separating 7-ACA by precipitation English name nationality invention creation / " PROCESS FOR THE PRODUCTION OF ROSETTES OR AGGLOMERATES OF 7-ACA AND FOR THE ISOLATION OF 7-ACA BY PRECIPITATION " 1. Bertelnadnik 2. Heimert Wegner 1.2. All Austrian · Living and domicile 1 · 22 Simon Perry Street, Oger, Austria 2 · Krusech, Austria The name (name) is set at 441 North Street. The Austrian commercial bank Olympian Line Ministry of Economics Intellectual Property Bureau employee consumer cooperative prints the applicant's nationality residence and residence (office) Representative name K-6, Austria, Austria 1. Jane · Klama 2 · Georges Grenerini This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 565563 Patent application No. 87108573 ~ Chinese manual amendment page (May 90) ^ 90 · 25 V. Description of the invention (9) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives. Table 1 Example of methanol [ml] Additive filter time Γπύηΐ 1 212 No additives 15 2 212 Polypropylenimide (e.g. amine) For example 6.5 ml P3 -Ferrocryl 7262Ri 1% solution 2 3 0 Polypropylene (amimine) For example 6.5 ml P3-Ferrocryl 7262 feet 1% solution 1.6 4 0 Organic carboxylic acid esters such as 49.5 ml ethyl acetate 2.1 5 0 Organic acid acids such as 10.6 ml Butyl acetate 1.1 6 212 Organic carboxylic acid esters such as 13.8 ml of butyl acetate 2.4 7 212 Organic carboxylic acid esters such as 64.4 ml of ethyl acetate 2.9 8 177 Polypropylene (amidamine) such as 0.81111 € 736? 241111 (€ > ^ ( : 1% solution of 0.8 9 177 polyamine such as 0.8 ml of 1% solution of C 592R (Cytec) 0.3 10 177 Polyamine such as 0.8 ml of 1% solution of C 567R (Cytec) 0.4 11 177 polymerized glycol ^ J ^ 3.2ml PEG 300R (Fluka) ^ 2.1 12 177 2.4 ml 1% solution of triethylene tetramine 3.2 13 177 m '" e.g. o 8 ml solution of ginseng- (2-aminoethyl) amine 10/0 3.2 14a 177 amino acid such as 0.8 ml L_Spermine acid. 1% solution of HC1 5.2 14 177 Amino acid such as 0.8 ml 1-A solution of 1% lysine 3.3 -12- Φ (Please read the notes on the back before filling this page) Standards are applicable to China National Standards (CNS) A4 specifications (210X297 mm) 565563 Patent Application No. 87108573 Chinese Specification Correction Page (May 90) V. Description of Invention (10) Examples 1 5 to 18 _-General Procedure At room temperature, 20.8 g of 7-ACA in the form of a sodium salt, 500 ml of water, and with or without the methanol (in ml) described in the following Table 2 with a pH of about 7.5 It was placed in a precipitation reactor and mixed with the additives described in Table 2 below. The p Η of the resulting mixture was adjusted to 5.5 by adding 20% sulfuric acid with stirring and held for about 20 minutes. The ρ η of the obtained suspension was adjusted to 3 · 8 ', and the suspension was cooled to 0. And stir for about 1 hour. The obtained crystal 7-ACA was filtered off, washed with 100 ml of water, and 100 ml of 70% methanol and 100 ml of methanol were dried at about 50 ° in a vacuum (about 10 mbar). About 16 hours. Filtration time (in minutes) is summarized in the following table 2 ° (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs. Table 2 Example Methanol [mil Additive Filtration Time [mini 15 150 No additives 14 16 100 Organic carboxylic acid esters such as 9 ml 1 butyl acetate 1.5 17 150 Polypropene (amidoamine) such as 6.51111-6 〇〇71 726211 (出 11) ^ 1) 1% solution 1.4 18 150 Polypropylene晞 (醯 amine) For example 3.2 ml of 1% solution of Rohafloc KF760R (Rhom) 3.0 19 100 Amino acid such as 0.8 ml of 1% solution of L-alanine 7.1 -13- bound paper size A4 ^ (21Qx297 male thin)

Claims (1)

5655631 ^ AS B8 C8 D8 92.9.02 1 Patent Application No. 08L 08573 Chinese Application Nasal Range Replacement (September 1992) Application for Patent Range 1. A 7-aminocephalosporin acid via precipitation (7_aca) A method for separation from a slightly acidic, neutral or alkaline solution having a pH higher than the isoelectric point of 7-ACA ', characterized by adding a) an organic ester of general formula Ri-COO- R2 II wherein Ri and R2 are the same or different and represent hydrogen, (Cl-4) alkyl'phenyl, hydroxyphenyl or (Ci-4) alkylphenyl; b) a polymeric diol of general formula III Compound HO ^ (〇.CHR1.CHR2) k-〇H ΙΠ Wherein and! ^ Is as defined above, and k represents an integer from 2 to 200; c) a polypropylene derivative based on cationic, anionic, or nonionic properties of the general formula IV- [CHRrCR2 (CO.XR3)] n- IV where X represents -0- or -NR!-, And R3 represents Ri or-(CR2R4) mZ, where Z represents -N ~ R4 -S〇3H -S〇3G COOHorCOO 0 m is an integer from 0 to 6, n Is an integer from 2 to 200,000, and Ri, R2, R4, and R5 are the same or different and represent hydrogen, (Ci-4) alkyl, phenyl, hydroxyphenyl, or (Ci_4) alkylphenyl; d) Amino acids of the general formula VIII and their esters R10-CH- (NR2R4) -COORl VIII 0 \ 53 \ 53387-920902 I The paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 565563 AB c D 6. The scope of the patent application where R1G represents hydrogen, (C ^) alkyl, phenyl, hydroxyphenyl or a group of the formula-(CH2) mX-R5, and the remaining substituents are as defined above. 2. The method according to item 1 of the scope of patent application, wherein the polymerized diol added during the precipitation process is a polyethylene glycol derivative or polypropylene glycol derivative 0 3. The method according to item 1 or 2 of the scope of patent application, It is characterized in that the additive is present in an amount of 1 ppm to 10% (v / v) in a basic, neutral or slightly acidic medium containing 7-ACA. ΟΛ53 \ 53387-920902 DOC \ 5-2-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)