CN112321582B - Synthesis of tebipenem side chain and refining method of intermediate - Google Patents
Synthesis of tebipenem side chain and refining method of intermediate Download PDFInfo
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- CN112321582B CN112321582B CN202011209174.0A CN202011209174A CN112321582B CN 112321582 B CN112321582 B CN 112321582B CN 202011209174 A CN202011209174 A CN 202011209174A CN 112321582 B CN112321582 B CN 112321582B
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Abstract
The invention provides a refining method of a tebipenem sidechain intermediate I, which comprises the following steps: dissolving the crude tebipenem side chain intermediate I with an organic solvent I, adding water, adjusting acid to make a substrate salify and transfer to a water phase, layering, and keeping the water phase; adding a reducing agent into the water phase, and stirring for decoloring; adding an organic solvent II into the water phase, adjusting the alkali to enable the substrate to be dissociated into the organic phase, filtering, layering and retaining the organic phase; and drying and concentrating the organic phase to obtain a refined product of the tebipenem side chain intermediate I. The refining method of the invention can remove part of small polar impurities and larger polar impurities in the tebipenem sidechain intermediate I, and remove the dark pigment generated by oxidation by adding a small amount of reducing agent (the decolorization is basically ineffective by using a conventional decolorization method such as adding activated carbon and the like), so that the purity of the obtained refined product of the tebipenem sidechain intermediate I is more than 97%. The refined product is easy to crystallize through hydrolysis reaction treatment to obtain white tebipenem sidechain solid, the product purity is more than 98%, and the solid stability is good.
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a method for synthesizing a tebipenem side chain and refining an intermediate.
Background
Tebipenem, developed and researched by gming pharmaceutical corporation in japan at 8 months in 2009, is marketed and, because of its low toxicity, is useful as a drug for children. Tebipenem acid can be used as an oral medicine after esterification protection, so that the tebipenem acid is the first hydrocarbon mycotoxin which can be orally taken at present. Can be used for treating infantile pneumonia, tympanitis and paranasal sinusitis, and compared with injection, the oral preparation has more convenient and wide clinical use.
Tebipenem side chain intermediate I (3-acetylthio-1- (1, 3-thiazol-2-yl) azetidine) is an important intermediate in the synthesis of tebipenem:
according to the existing relatively mature synthesis route (reference: J.Antibiott.59 (4):241-247,2006), the side chain of tebipenem is synthesized by adopting a high-temperature reaction at 100 ℃, so that a lot of oxidation or degradation impurities are easily generated after a long time, and finally the obtained product has the problems of dark color, a lot of impurities in the product and the like, so that the side chain of tebipenem prepared by the next step of reaction has the disadvantages of reaction impurity, difficult crystallization, dark color of the obtained solid and easy moisture absorption.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a refining method of a tebipenem sidechain intermediate, which has the advantages of cheap and easily-obtained raw materials and auxiliary materials, simple operation, good quality of obtained products, low cost and suitability for industrial production.
A refining method of tebipenem side chain intermediates comprises the following steps:
(1) dissolving the crude tebipenem side chain intermediate I with an organic solvent I, adding water, adjusting acid to make a substrate salify and transfer to a water phase, layering, and keeping the water phase;
(2) adding a reducing agent into the water phase, and stirring for decoloring;
(3) adding an organic solvent II into the water phase, adjusting the alkali to enable the substrate to be dissociated into the organic phase, filtering, layering and retaining the organic phase;
(4) and drying and concentrating the organic phase to obtain a refined product of the tebipenem side chain intermediate I.
The structure of the tebipenem side chain intermediate I is as follows:
in the refining method of the tebipenem sidechain intermediate, the preparation method of the tebipenem sidechain intermediate I is known in the prior art, and a crude tebipenem sidechain intermediate I product with the purity of about 80-85% and brown or dark brown oily liquid can be prepared by adopting the method reported in J.Antibiott.59 (4):241-247, 2006.
In the step (1):
preferably, the organic solvent I comprises one or more of ethyl acetate, dichloromethane, chloroform, toluene and xylene.
Preferably, the acid is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and oxalic acid.
Preferably, the pH value of the acid is adjusted to be 0.5-4.5; more preferably 0.5 to 3.
In the step (2):
preferably, the reducing agent comprises one or more of particles or powders of magnesium, aluminium, zinc, iron; more preferably, magnesium powder or magnesium chips.
Preferably, the mass ratio of the reducing agent to the crude tebipenem sidechain intermediate I is (0.001-0.01): 1. more preferably (0.001 to 0.005): 1. the method of the invention can realize the decolorization of the substrate by adopting a very small amount of reducing agent.
Preferably, the decoloring is carried out under the condition of stirring, the decoloring temperature is 20-40 ℃, and the decoloring time is 10-60 minutes.
In the step (3):
preferably, the organic solvent II comprises one or more of ethyl acetate, dichloromethane, trichloromethane, toluene and xylene.
Preferably, the alkali is one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and ammonia water.
Preferably, the pH value of the alkali is adjusted to be 8.0-10.0; more preferably 8.5 to 9.5.
Preferably, in the step (4), the drying agent used in the organic phase is one or a mixture of more of anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride, activated molecular sieve and the like; more preferably anhydrous magnesium sulfate. Drying for 10-60 min; more preferably 20 to 50 min.
Specifically, the specific operation process of step (4) is as follows:
and adding a drying agent into the organic phase, drying for 10-60 min, filtering, and concentrating the filtrate under reduced pressure to obtain the refined product of the tebipenem side chain intermediate I.
A synthesis method of a tebipenem side chain comprises the following steps: the method comprises the following steps of preparing a tebipenem side chain intermediate I crude product by using 3-methylsulfonyloxy-1- (1, 3-thiazole-2-yl) azetidine and potassium thioacetate as raw materials, refining by using the refining method of any one technical scheme to obtain a refined product of the tebipenem side chain intermediate I, and hydrolyzing the refined product to obtain the tebipenem side chain.
The tebipenem sidechain structure is as follows:
compared with the prior art, the invention has the beneficial effects that:
according to the refining method, the crude tebipenem sidechain intermediate I is refined, so that part of small-polarity impurities and large-polarity impurities in the crude tebipenem sidechain intermediate I can be removed, a small amount of reducing agent is added so that dark pigment generated by oxidation can be removed (the decolorization is basically ineffective by using a conventional decolorization method such as adding activated carbon and the like), and the obtained refined tebipenem sidechain intermediate I is colorless oily liquid, and the purity of the refined tebipenem sidechain intermediate I is over 97 percent. In addition, the refining method has the advantages of cheap and easily-obtained raw and auxiliary materials, simple operation, good product quality and low cost, and is suitable for industrial production. The refined Taibipenem sidechain intermediate I prepared by the refining method is easily crystallized through hydrolysis reaction treatment to obtain white Taibipenem sidechain solid, the purity of the product is more than 98%, and the solid stability is good.
The method has the advantages of cheap and easily-obtained raw and auxiliary materials, simple operation, good product quality and low cost, and is suitable for industrial production.
Drawings
FIG. 1 is a MS spectrum of refined Taibipenem sideline intermediate I prepared in example 1 of the present invention.
FIG. 2 is a nuclear magnetic H spectrum of the tebipenem sidechain obtained in example 4 of the present invention;
FIG. 3 is a nuclear magnetic C spectrum of the side chain of tebipenem prepared in example 4 of the present invention.
Detailed Description
In order that those skilled in the art will better understand the present invention, the present invention will be further described in detail with reference to the following examples, but the present invention is not limited thereto. Any equivalent alterations in the field made in accordance with the present disclosure are intended to be within the scope of the present invention.
Example 1:
40g of crude tebipenem sidechain intermediate I (dark brown, 85% pure) was added to a 500ml four-necked flask, 160ml of methylene chloride was added and dissolved under stirring at room temperature, 100ml of water was added, about 40ml of 10% aqueous phosphoric acid solution was added dropwise, pH was adjusted to approximately 3.0, stirring was carried out for 10min, and the layers were separated. 0.1g of magnesium chips was added to the aqueous phase, and the mixture was stirred at room temperature for 0.5 hour, whereby the solution gradually changed from dark brown to pale yellow and almost colorless. Adding 150ml of dichloromethane into the water phase, dropwise adding about 35ml of 20% sodium carbonate solution while stirring, adjusting the pH value to be about 9.3, stirring for 10min, filtering, standing the filtrate for layering, adding 10g of anhydrous magnesium sulfate into the organic phase, drying for 20min, filtering, and concentrating the filtrate at 45 ℃ under reduced pressure to obtain 32g of light yellow oily liquid tebipenem side chain intermediate I with the HPLC purity of 97.43%. (Mass Spectrometry: attached FIG. 1)
Example 2:
40g of crude tebipenem sidechain intermediate I (dark brown, purity 82%) is added to a 500ml four-necked flask, 160ml of ethyl acetate is added and dissolved under stirring at room temperature, 100ml of water is added, about 37ml of 10% sulfuric acid aqueous solution is added dropwise, pH is adjusted to be approximately 1.2, stirring is carried out for 10min, and layers are separated. 0.1g of magnesium powder was added to the aqueous phase, and the mixture was stirred at room temperature for 0.5 hour, whereby the solution gradually became colorless from dark brown. Adding 150ml of ethyl acetate into the water phase, dropwise adding about 48ml of 20% potassium bicarbonate aqueous solution while stirring, adjusting the pH to be approximately equal to 8.8, stirring for 10min, filtering, standing and layering the filtrate, adding 10g of anhydrous magnesium sulfate into the organic phase, drying for 20min, filtering, and concentrating the filtrate at 45 ℃ under reduced pressure to obtain 31g of colorless oily liquid tebipenem sidechain intermediate I with the HPLC purity of 96.82%.
Example 3:
40g of crude tebipenem sidechain intermediate I (dark brown, 85% pure) was added to a 500ml four-necked flask, 160ml of toluene was added and dissolved under stirring at room temperature, 100ml of water was added, about 68ml of 10% hydrochloric acid was added dropwise, pH was adjusted to approximately 0.8, stirring was carried out for 10min, and the layers were separated. 0.1g of magnesium powder was added to the aqueous phase, and the mixture was stirred at room temperature for 0.5 hour, whereby the solution gradually became colorless from dark brown. Adding 150ml of toluene into the water phase, dropwise adding about 44ml of 20% sodium carbonate solution while stirring, adjusting the pH value to be approximately 8.9, stirring for 10min, filtering, standing the filtrate for layering, adding 10g of anhydrous magnesium sulfate into the organic phase, drying for 20min, filtering, and concentrating the filtrate at 45 ℃ under reduced pressure to obtain 32g of colorless oily liquid tebipenem side chain intermediate I with the HPLC purity of 97.68%.
Comparative example 1:
the magnesium turnings in example 1 were replaced with 5g of activated carbon, stirred at room temperature for 1 hour, and filtered, and the color of the filtrate was not changed and remained dark brown. The remaining material steps and reaction conditions were as in example 1, and the tebipenem sidechain intermediate i was finally obtained as an oil in a dark brown color with a purity of 97.36%.
Comparative example 2
In the same manner as in comparative example 1, 5g of activated carbon was added, and the mixture was stirred at 50 ℃ for 1 hour, followed by filtration to give a dark brown oil having a purity of 97.30%.
Example 4:
the tebipenem sidechain intermediate I (30g, 139mmol) prepared in example 1 was prepared according to the method for preparing 3-Mercapto-1- (1,3-thiazolin-2-yl) azetidine hydrochloride (1) in the literature (Synthesis and pharmaceutical students of drug entities for the Development of organic Carbapenem, L-084J. Antibiot.59(4):241-247,2006) (last part of p244, first part of p 245) to obtain 26.3g of tebipenem sidechain as a white granular solid in 90.12% yield and 98.21% purity. (Nuclear magnetic H spectrum: FIG. 2, nuclear magnetic C: FIG. 3)
Comparative example 3
The hydrolysis reaction of example 4 was carried out using tebipenem sidechain intermediate i obtained in comparative example 1 to obtain tebipenem sidechain as light brown or yellowish solid particles (yield 89.85%, purity 98.32%).
Comparative example 4
40g of crude tebipenem intermediate I (dark brown, 85% purity) was taken and directly hydrolyzed by the method of example 4 without purification to obtain 23.5g of tebipenem intermediate in the form of light brown or earthy yellow block or other heterogeneous solid, yield 60.3% and purity 93.43%.
Moisture absorption test example 1:
when the tebipenem sidechains prepared in example 4 and comparative example 4 were left at room temperature (about 25 ℃, humidity of 70%) for 12 hours, the increase in water content of the tebipenem sidechain prepared in example 4 was insignificant, and compared to 0 hours, the increase in water content was 1% and the tebipenem sidechain was always in a uniform granular form and had good solid appearance. The tebipenem sidechain prepared in comparative example 4 increased in water content by 8% after standing for 12 hours, and was divided into oily substances after moisture absorption, which were difficult to store and use.
Stability test example 2:
placing the side chain samples of tebipenem prepared in example 4 and comparative example 4 in a constant temperature and humidity box, and keeping the temperature at 40 +/-2 ℃; humidity 75% + -5, periodic sampling and inspection, the experimental results are shown in the following table:
as can be seen from stability tests, the tebipenem sidechain sample obtained by refining by the method of the invention has better stability, and the purity is basically unchanged after the sample is placed for 3 months. The tebipenem side chain sample obtained from the intermediate I without refining is obviously reduced in purity after being placed for 3 months.
Claims (9)
1. A refining method of a tebipenem side chain intermediate I is characterized by comprising the following steps:
(1) dissolving the crude tebipenem side chain intermediate I with an organic solvent I, adding water, adjusting acid to make a substrate salify and transfer to a water phase, layering, and keeping the water phase;
(2) adding a reducing agent into the water phase, and stirring for decoloring;
(3) adding an organic solvent II into the water phase, adjusting the alkali to enable the substrate to be dissociated into the organic phase, filtering, layering and retaining the organic phase;
(4) drying and concentrating the organic phase to obtain a refined product of the tebipenem side chain intermediate I;
the structure of the tebipenem side chain intermediate I is as follows:
in the step (2), the reducing agent is one or more of particles or powder of magnesium, aluminum and zinc.
2. The method for purifying tebipenem sidechain intermediate I as claimed in claim 1, wherein in step (1), the organic solvent I is one or more of ethyl acetate, dichloromethane, chloroform, toluene and xylene.
3. The method for purifying tebipenem intermediate I as claimed in claim 1, wherein in step (1), the acid is one or more of sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid and oxalic acid.
4. The process for purifying tebipenem sidechain intermediate I as claimed in claim 1, wherein in the step (1), the pH is adjusted to 0.5-4.5.
5. The method for refining the tebipenem sidechain intermediate I as claimed in claim 1, wherein in the step (2), the mass ratio of the reducing agent to the crude tebipenem sidechain intermediate I is (0.001-0.01): 1.
6. the method for purifying tebipenem sidechain intermediate I as claimed in claim 1, wherein in step (3), the organic solvent II is one or more of ethyl acetate, dichloromethane, chloroform, toluene and xylene.
7. The method for refining the tebipenem sidechain intermediate I as claimed in claim 1, wherein in the step (3), the alkali is one or more of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and ammonia water.
8. The process for purifying tebipenem intermediate I as claimed in claim 1, wherein in step (3), the pH of the solution is adjusted to 8.0-10.0.
9. A synthetic method of a tebipenem side chain is characterized by comprising the following steps: preparing a crude tebipenem side chain intermediate I by using 3-methylsulfonyloxy-1- (1, 3-thiazole-2-yl) azetidine and potassium thioacetate as raw materials, refining by using the refining method of any one of claims 1 to 8 to obtain a refined product of the tebipenem side chain intermediate I, and deacetylating the refined product under a hydrolysis condition to obtain the tebipenem side chain, wherein the structure of the tebipenem side chain is as follows:
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| CN102250080B (en) * | 2011-04-26 | 2015-06-03 | 广州白云山制药股份有限公司广州白云山制药总厂 | Preparation method of 1-(4, 5-dihydro-2-thiazolinyl)-3-mercaptoazetidine hydrochloride |
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