CN105859746A - Synthesis method for aspoxicillin - Google Patents

Synthesis method for aspoxicillin Download PDF

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Publication number
CN105859746A
CN105859746A CN201610163858.9A CN201610163858A CN105859746A CN 105859746 A CN105859746 A CN 105859746A CN 201610163858 A CN201610163858 A CN 201610163858A CN 105859746 A CN105859746 A CN 105859746A
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China
Prior art keywords
aspoxicillin
solution
synthesis
temperature
amoxicillin
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CN201610163858.9A
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Chinese (zh)
Inventor
谢永居
郑裕义
余明远
王玉娟
龚杰
周忠波
余翔
胡涛
杨玉平
刘霞
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HAINAN GENERAL SANYANG PHARMACEUTICAL CO Ltd
JINGDEZHEN FUXIANG PHARMACEUTICAL CO Ltd
Original Assignee
HAINAN GENERAL SANYANG PHARMACEUTICAL CO Ltd
JINGDEZHEN FUXIANG PHARMACEUTICAL CO Ltd
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Priority to CN201610163858.9A priority Critical patent/CN105859746A/en
Publication of CN105859746A publication Critical patent/CN105859746A/en
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D499/44—Compounds with an amino radical acylated by carboxylic acids, attached in position 6
    • C07D499/48—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical
    • C07D499/58—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical
    • C07D499/64—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms
    • C07D499/68—Compounds with an amino radical acylated by carboxylic acids, attached in position 6 with a carbon chain, substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, attached to the carboxamido radical substituted in alpha-position to the carboxamido radical by nitrogen atoms with aromatic rings as additional substituents on the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D499/04—Preparation

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention discloses a synthesis method for aspoxicillin. The method comprises the following steps: (1) dissolving anhydrous amoxicillin and triethylamine in dichloromethane, adding trimethylchlorosilane drop by drop at a temperature of -10 DEG C or below and carrying out a reaction as temperature is maintained at -15 to 10 DEG C so as to obtain a solution A; (2) reacting potassium (R)-[(3-ethoxy-1-methyl-3-oxoprop-1-enyl)amino]phenylacetate, chloroformate and N-methylmorpholine in dichloromethane at a temperature of -10 DEG C or below so as to obtain a solution B; and (3) adding the solution B into the solution A drop by drop at a temperature of -10 DEG C or below and carrying out after-treatment after completion of the reaction so as to obtain the aspoxicillin product. The method has creativity; in the whole reaction process, after-treatment is not needed, and the solution A can be directly reacted with the solution B; so the method has the characteristics of simple operation, convenient after-treatment, shortened reaction period, low impurity content, high yield and the like and is suitable for mass production.

Description

A kind of method synthesizing aspoxicillin
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to a kind of side synthesizing aspoxicillin Method.
Background technology
Aspoxicillin, chemical name: (2S, 5R, 6R)-6-[(2R)-2-[(2R)-2-amino-3-(N-methylamino first Acyl) propionamido-]-2-(p-hydroxyphenyl) acetylamino]-3,3-dimethyl-7-oxo-4-thia-1-azepine pair Ring [3,2,0]-heptane-2-carboxylic acid trihydrate, the external trade name of English name: Aspoxicillin: Doyle Chinese phonetic alphabet name: APu Xi Lin, its structure is as follows:
Compound (I).
Aspoxicillin is day first injection amino acid pattern in the world of Honda limit drugmaker exploitation Semisynthetic penicillin medicine, 1987 in Japan's Initial Public Offering.Can be clinically used for treating septicemia, Infective endocarditis, the secondary infection of wound, scald, surgical wound etc., pharyngolaryngitis, tonsil Inflammation, acute bronchitis, pneumonia, pulmonary abscess, the secondary infection of chronic respiratory system diseases, peritoneum Inflammation, cholecystitis, cholangitis, otitis media, nasal sinusitis, lower ganathitis.This medicine is currently located in China In the new drug development stage, there is good development prospect.
At present, the synthesis technique of aspoxicillin is broadly divided into three kinds by raw material difference:
(1) D-Asp-β-Methanamide and amido protecting agent 2-Nitrobenzol sulfur chlorine (are called for short NPS-Cl) reaction, then under the effect of DCC, by activated carboxylic, then through condensation, remove-insurance Protecting, six-step process, eventually passes pillar layer separation method, obtains target compound (The Journal altogether of antibiotics 1983,36(2),147-154.).In this route, 2-Nitrobenzol sulfur chlorine toxicity is very big, has Dense stink is big to human injury.
(2) acyl chlorides synthetic method (US4053609), uses thionyl chloride reaction to obtain 2-aminomethylamine Carbon propionic, then obtain aspoxicillin through being acylated, be condensed, being hydrogenated with Deprotection.This route Due to thionyl chloride and the use of hydrogenation, safety is made to reduce.
(3) activity anhydride method (Tang Guangan, the most inspired, Zou Qiaogen. semi-synthetic penicillins antibiotic The Improved synthesis of aspoxicillin, Chinese Journal of New Drugs, 2009, volume 18, the 10th phase), with D-ASP and Utimox are raw material, with 2-Nitrobenzol sulfur chlorine as amido protecting Base, is prepared as anhydride with pivaloyl chloride, then through condensation, deprotection prepares aspoxicillin.This route Need nonetheless remain for using 2-Nitrobenzol sulfur chlorine, this reagent needs to be manufactured separately, and which increases the cycle of preparation, And toxicity is very big, and last deprotection is the most inconvenient, and yield is the highest.
Summary of the invention
The synthesis technique that the present invention is directed to existing aspoxicillin is unstable, and poor repeatability is not suitable for work The problem that industry produces, it is provided that a kind of technological operation is simple, is not required to use the toxicity such as 2-Nitrobenzol sulfur chlorine Reagent, yield is high, and product purity is high, and impurity is few, is suitable for industrial aspoxicillin synthetic method.
It is an object of the invention to realize by following technical solution:
A kind of method synthesizing aspoxicillin, comprises the steps:
Step one: amoxicillin (compound shown in Formula II) is in a certain proportion of alcohol and the effect of toluene Under, temperature rising reflux removes water.After a period of time, under nitrogen protection, cooling, filter, dry anhydrous Amoxicillin.
Step 2: anhydrous amoxicillin (compound shown in Formula II) and triethylamine are dissolved in dichloromethane In alkane, under low temperature, drip TMSCl (trim,ethylchlorosilane) dichloromethane solution, low-temperature protection one section Time, heating and heat preservation a period of time obtains solution A (containing the compound shown in formula III)；
Step 3: carry out meanwhile in step 2, in dichloromethane, dane potassium salts (formula IV Shown compound) and chloro-formate (compound shown in Formula V), N-methylmorpholine is through low-temp reaction Obtain solution B (containing the compound shown in Formula IV).
Step 4: solution B is added dropwise under low temperature solution A, after reaction terminates, adds water, point Layer, the saturated NaHCO of organic facies3Aqueous solution extraction, merges aqueous phase, regulates pH with hydrochloric acid solution Crystallize obtains final aspoxicillin product, shown in formula I.
The reaction scheme of the present invention is as follows:
First Utimox is carried out being dehydrated and carries out silanization protection again, and then by this technique React, with dane potassium salts and chloro-formate, the activity anhydride formed to carry out reacting direct crystallize and obtain high-purity Aspoxicillin.
Below preferred embodiments of the present invention are described further:
In step (1), as preferably, described alcohol select the one in isopropanol, n-butyl alcohol or Mixing.The mass ratio of described alcohol and toluene is (3:2)-(4:1).In step one, return time For 0.5-1h.
In step 2, as preferably, described triethylamine is (2-5) with the mol ratio of anhydrous amoxicillin: 1, more preferably (2.25-2.5): 1.In step 2, triethylamine is as acid binding agent, Ke Yixun Speed is reacted with the HCl of generation in system, it is ensured that is swift in response and carries out towards positive direction.
In step 2, as preferably, described TMSCl is (2-4) with the mol ratio of anhydrous amoxicillin: 1, more preferably (2.2-2.5): 1.In step 2, TMSCl, as protective agent, is used for protecting Protect the primary amine groups in anhydrous amoxicillin.
In step 2, TMSCl can directly drip, it is possible to uses the dropping of solution form, uses solution shape During formula dropping, solvent typically uses the solvent identical with reaction dissolvent.As preferably, drip TMSCl Temperature be-30～-15 DEG C, more preferably-20～-15 DEG C；After dropping, reaction temperature It is preferably-5～10 DEG C.
In step 3, as preferably, described dane potassium salts with the mol ratio of amoxicillin in step 2 is (1-5): 1, more preferably (1.5-2.5): 1.Described chloro-formate and A Moxi in step 2 The mol ratio of woods is (1.5-2.5): 1., described N-methylmorpholine and the rubbing of amoxicillin in step 2 Your ratio is (0.05-1): 1, more preferably (0.05-0.08): 1.
In step 3, described chloro-formate use dropping mode add, dropping temperature be preferably-30～ -15 DEG C, it is ensured that during dropping, system temperature is less than-15 DEG C, it is to avoid the generation of side reaction.Dropping After, reaction temperature is-25～-15 DEG C.
In step 4, solution B is added dropwise in solution A, dropping temperature preferably-30～-15 DEG C, During ensureing dropping, system temperature is less than-15 DEG C, it is to avoid the generation of side reaction；Dripping of solution B Adding the time is 1-3h.After dropping, HPLC tracking reaction process can be passed through.
In step 4, the mass percent concentration of the hydrochloric acid of employing is 10-30%.Regulation pH value range Between 4-6, more preferably 4-5.
Compared with prior art, beneficial effects of the present invention is embodied in:
The method of the present invention has originality, in whole course of reaction, it is not necessary to post processing, and can be direct Reactant liquor A and reactant liquor B is reacted, there is simple to operate, convenient post-treatment, reaction week Phase shorten, impurity few, yield high, be suitable to industrial mass production.
Accompanying drawing explanation
Fig. 1 is the product high-efficient liquid phase chromatogram (detecting by Japanese Pharmacopoeia) that embodiment 1 prepares.
Detailed description of the invention
Further describe the present invention by the following examples, but these embodiments be merely illustrative, Protection scope of the present invention is not constituted any restriction, it will be apparent to a skilled person that According to the present invention spirit made replacement, amendment each fall within protection scope of the present invention.
Embodiment 1:
80g Utimox, 700g isopropanol, 300g first is added in 2000ml bottle Benzene, stirring, temperature rising reflux divides water 0.5 hour.The lower cooling rapidly of nitrogen protection, filters, and filter cake is used A small amount of anhydrous isopropyl alcohol washing, at 45 DEG C, vacuum drying obtains anhydrous amoxicillin.
Taking above-mentioned prepared anhydrous amoxicillin 20g, anhydrous DCM 120g, 2.25eq is (with anhydrous The amount of amoxicillin calculates) TEA, cool to-20 DEG C, (2.2eq, with anhydrous for dropping TMSCl The amount of amoxicillin calculates) (<-15 DEG C), it is warming up to 0～10 DEG C of insulation 1h after dropping, obtains molten Liquid A.
By the N-methylmorpholine of dane potassium salts (1.5eq of amoxicillin), dichloromethane and catalytic amount (Ah The 0.05eq of Amdinocillin), stirring cooling-20 DEG C, temperature control less than-15 DEG C drip chloro-formate (dane potassium salts 1.05eq), drip complete-15 DEG C and react 3 hours, obtain solution B.
Less than-15 DEG C, solution B being added dropwise to solution A, time for adding is that 1.5h, HPLC follow the tracks of instead Should, after terminating, add 100ml water, separatory, organic facies 40ml NaHCO3Solution extracts, Merge aqueous phase, be stirred vigorously down, be that 20%HCl aqueous solution regulates aqueous phase pH with mass percent concentration Value is to pH=4.5, temperature control 0～5 DEG C, crystallize 4h, product yield 85%, and product meets JP standard (HPLC Test spectrogram is shown in Fig. 1), nuclear magnetic data is consistent with existing standard product.
Embodiment 2:
80g Utimox, 700g isopropanol, 300g first is added in 2000ml bottle Benzene, stirring, temperature rising reflux divides water 0.5 hour.The lower cooling rapidly of nitrogen protection, filters, and filter cake is used A small amount of anhydrous isopropyl alcohol washing, at 45 DEG C, vacuum drying obtains anhydrous amoxicillin.
Taking above-mentioned prepared anhydrous amoxicillin 20g, anhydrous DCM 120g, 2.5eq is (with anhydrous The amount of amoxicillin calculates) TEA, cool to-20 DEG C, (2.5eq, with anhydrous for dropping TMSCl The amount of amoxicillin calculates) (<-15 DEG C), it is warming up to 0～10 DEG C of insulation 1h after dropping, obtains molten Liquid A.
By dane potassium salts (1.5eq of amoxicillin), acetonitrile and the N-methylmorpholine (A Moxi of catalytic amount The 0.05eq of woods), stirring cooling-20 DEG C, temperature control less than-15 DEG C drip chloro-formate (dane potassium salts 1.05eq), drip complete-15 DEG C and react 3 hours, obtain solution B.
Less than-15 DEG C, solution B being added dropwise to solution A, time for adding is that 1.5h, HPLC follow the tracks of instead Should, after terminating, add 100ml water, separatory, organic facies 40ml NaHCO3Solution extracts, Merge aqueous phase, be stirred vigorously down, be that 20%HCl aqueous solution regulates aqueous phase pH with mass percent concentration Value is to pH=4.5, temperature control 0～5 DEG C, crystallize 4h, product yield 87%, and product meets JP standard.
Embodiment 3:
80g Utimox, 700g n-butyl alcohol, 300g first is added in 2000ml bottle Benzene, stirring, temperature rising reflux divides water 0.5 hour.The lower cooling rapidly of nitrogen protection, filters, and filter cake is used A small amount of anhydrous isopropyl alcohol washing, at 55 DEG C, vacuum drying obtains anhydrous amoxicillin.
Taking above-mentioned prepared anhydrous amoxicillin 20g, anhydrous DCM 120g, 2.25eq is (with anhydrous The amount of amoxicillin calculates) TEA, cool to-30 DEG C, (2.2eq, with anhydrous for dropping TMSCl The amount of amoxicillin calculates) (<-15 DEG C), it is warming up to 0～10 DEG C of insulation 1h after dropping, obtains molten Liquid A.
By dane potassium salts (1.5eq of amoxicillin), acetonitrile and the N-methylmorpholine (A Moxi of catalytic amount The 0.08eq of woods), stirring cooling-20 DEG C, temperature control less than-15 DEG C drip chloro-formate (dane potassium salts 1.05eq), drip complete-15 DEG C and react 3 hours, obtain solution B.
Less than-15 DEG C, solution B being added dropwise to solution A, time for adding is that 2.0h, HPLC follow the tracks of instead Should, after terminating, add 100ml water, separatory, organic facies 40ml NaHCO3Solution extracts, Merge aqueous phase, be stirred vigorously down, be that 20%HCl aqueous solution regulates aqueous phase pH with mass percent concentration Value is to pH=4.5, temperature control 0～5 DEG C, crystallize 4h, product yield 88%, and product meets JP standard.

Claims (10)

1. the method synthesizing aspoxicillin, it is characterised in that comprise the steps:
(1) anhydrous amoxicillin and triethylamine are dissolved in dichloromethane, less than-10 DEG C droppings three Methylchlorosilane ,-15～10 DEG C of insulation reaction, obtain solution A；
(2) in dichloromethane, by dane potassium salts and chloro-formate, N-methylmorpholine below-10 DEG C Reaction, obtains solution B；
(3) below-10 DEG C, solution B being added dropwise in solution A, reaction terminates, post processing Obtain aspoxicillin product.
The method of synthesis aspoxicillin the most according to claim 1, it is characterised in that described Anhydrous amoxicillin is prepared by following method: by amoxicillin under the effect of alcohol and toluene, rises Temperature backflow is except water；Described alcohol selects the one in isopropanol, n-butyl alcohol or mixing, alcohol and toluene Mass ratio is (3:2)-(4:1).
The method of synthesis aspoxicillin the most according to claim 1, it is characterised in that described Triethylamine is (2-5) with the mol ratio of anhydrous amoxicillin: 1.
The method of synthesis aspoxicillin the most according to claim 1, it is characterised in that described Trim,ethylchlorosilane is (2-4) with the mol ratio of anhydrous amoxicillin: 1.
5. according to the method for the synthesis aspoxicillin described in claim 1 or 4, it is characterised in that The temperature of dropping trim,ethylchlorosilane is-30～-15 DEG C；After dropping, reaction temperature is-5～10 ℃。
The method of synthesis aspoxicillin the most according to claim 1, it is characterised in that described Dane potassium salts is (1-5) with the mol ratio of anhydrous amoxicillin: 1.
The method of synthesis aspoxicillin the most according to claim 1, it is characterised in that described Chloro-formate is (1.5-2.5) with the mol ratio of anhydrous amoxicillin: 1.
The method of synthesis aspoxicillin the most according to claim 1, it is characterised in that described N-methylmorpholine is (0.05-1) with the mol ratio of anhydrous amoxicillin: 1.
The method of synthesis aspoxicillin the most according to claim 1, it is characterised in that described Chloro-formate uses the mode of dropping to add, and dropping temperature is-30～-15 DEG C, after dropping, instead Answering temperature is-25～-15 DEG C.
The method of synthesis aspoxicillin the most according to claim 1, it is characterised in that by molten Liquid B is added dropwise in solution A, and dropping temperature is-30～-15 DEG C.
CN201610163858.9A 2016-03-22 2016-03-22 Synthesis method for aspoxicillin Pending CN105859746A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1246495A (en) * 1967-12-18 1971-09-15 Bayer Ag Penicillins and their production
US3873523A (en) * 1972-12-15 1975-03-25 Parke Davis & Co Derivatives of ampicillin
DE2612926A1 (en) * 1976-03-26 1977-10-06 Boehringer Mannheim Gmbh Broad spectrum antibacterial hydantoinyl-acetyl-ampicillin derivs. - prepd. by reacting hydantoinyl-acetic acids with phenyl-glycine and (6)-amino-penicillanic acid
EP0294789A1 (en) * 1987-06-11 1988-12-14 KRKA, tovarna zdravil, n.sol.o Process for preparing 6-/D(-)-Alpha-(4-ethyl-2,3-dioxo-1-piperazine-carboxamido)-phenylacetamido/pennicillanic acid
CN103333180A (en) * 2013-07-05 2013-10-02 湖南三清药业有限公司 Preparation method of aspoxicillin

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1246495A (en) * 1967-12-18 1971-09-15 Bayer Ag Penicillins and their production
US3873523A (en) * 1972-12-15 1975-03-25 Parke Davis & Co Derivatives of ampicillin
DE2612926A1 (en) * 1976-03-26 1977-10-06 Boehringer Mannheim Gmbh Broad spectrum antibacterial hydantoinyl-acetyl-ampicillin derivs. - prepd. by reacting hydantoinyl-acetic acids with phenyl-glycine and (6)-amino-penicillanic acid
EP0294789A1 (en) * 1987-06-11 1988-12-14 KRKA, tovarna zdravil, n.sol.o Process for preparing 6-/D(-)-Alpha-(4-ethyl-2,3-dioxo-1-piperazine-carboxamido)-phenylacetamido/pennicillanic acid
CN103333180A (en) * 2013-07-05 2013-10-02 湖南三清药业有限公司 Preparation method of aspoxicillin

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
唐广安: "半合成青霉素类抗生素阿扑西林的合成改进", 《中国新药杂志》 *
张峥: "阿扑西林合成新工艺研究", 《中国抗生素杂志》 *
曹观坤: "《药物化学选论》", 28 February 1993, 中国医药科技出版社 *

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Application publication date: 20160817