CN102558094A - Method for preparing ceftaroline side-chain acid - Google Patents
Method for preparing ceftaroline side-chain acid Download PDFInfo
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Abstract
The invention discloses a method for preparing ceftaroline side-chain acid shown as a formula (I). The method comprises the following steps of: performing oximation reaction on 5-amino-1,2,4-thiadiazole-3-acetamide derivative and nitrite under catalysis of concentrated hydrochloric acid, performing esterification reaction with an ethylation reagent in the presence of organic alkali, dissolving in an aqueous solution of inorganic alkali, and thus obtaining the ceftaroline side-chain acid. The method has the advantages of mild reaction conditions, simplicity and convenience in operation, good reaction selectivity, high yield, short production period, low 'three-waste' quantity, easiness in industrialization and high implementation value and social and economic benefits.
Description
(1) technical field
The present invention relates to the preparation method of a kind of cephalo Lorraine side-chain acid.
(2) technical background
In recent years, the antibiotic resistance problem is on the rise.Continuous enhancing along with bacterial drug resistance; The strong resistance of methicillin resistance golden staphylococci (MRSA) particularly; Make the research and development of new antibiotic meet with challenge; The microbiotic of anti-MRSA commonly used is vancomyein and Linezolid at present, but these two kinds of microbiotic are all more weak to the activity of Gram-negative bacteria.
Cephalo Lorraine ester (Ceftaroline Fosamil); Develop by the Japan pharmacy of military field (TakedaPharmaceutical) company; U.S. Forest Laboratories (Cerexa) company obtains market and authorizes; In Nikkei united states drug food control office approval listing October 29 in 2010, belong to the 5th generation cephalosporin analog antibiotic, it all has anti-microbial activity to streptococcus aureus (MRSA), many resistances streptococcus pneumoniae and multiple Gram-negative bacteria.Cephalo Lorraine ester is cracked into cephalo Lorraine (Ceftaroline) very soon in human body; Thereby performance drug effect; Be mainly used in treatment adult's acquired bacterial enteritis of community (CABP) and acute bacterial skin and skin histology and infect (ABSSSI); Comprise that X-1497 tolerance aurococcus (MRSA) infects, and can substitute " vancomyein " in these areas.
Ester cephalo Lorraine, cephalo Lorraine
Cephalo Lorraine side-chain acid----(Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetate (I) is the key intermediate for preparing cephalo Lip river quinoline (ester); Belong to 5-amino-1; 2,4-thiadiazoles-3-(hydroxyl imido grpup) acetogenin about the document compound method of cephalo Lorraine side-chain acid (I) is: GB2094794 and Hebei industrial technology; 2008; 25,361-362 has successively reported with the malonamide nitrile to be raw material, through oximate, ethylization, POCl3 dehydration, ammonia separate, bromo, cyclization, alkaline hydrolysis obtain cephalo Lorraine side-chain acid.
This technology has been used poisonous and harmful reagent such as POCl3, bromine, and " three wastes " amount is big and step is comparatively loaded down with trivial details, yield is 18%; The cyan-hydrolysis of final step, GB101987837 have been reported with Lithium Hydroxide MonoHydrate and have been made alkali, add phase-transfer catalyst, and hydrolysis reaction obtains cephalo Lorraine side-chain acid.In addition, JP2003201285 has reported with the hydrated barta hydrolysis reaction and has obtained cephalo Lorraine side-chain acid, but the yield of this step reaction is merely 53%.
The document relevant with the present invention, promptly about 5-amino-1,2, the compound method of 4-thiadiazoles-3-(hydroxyl imido grpup) acetogenin mainly contains:
1, University of Anhui's journal (natural science edition); 2007; 31 (6), 74-77 has reported with the ethyl cyanacetate to be starting raw material, through oximate, methylate, again oximate, oxime hydroxyl protection, cyclization, formylation, hydrolysis obtain SCE 2787 side-chain acid----(Z)-(5-amino-1 for 2-; 2,4-thiadiazoles-3-yl)-2-methoxy imino guanidine-acetic acid.Repeatedly relate to radical protection and protective reaction in this route reaction, route is more loaded down with trivial details, and has used the unfriendly reagent of environment such as thionyl chloride.
2, JP62205066 and J.Antibiot., 2000,53 (10): 1053-1070 has reported with the malonamide nitrile to be raw material, with salicylaldhyde, 1-chlorine pyrroles-2; 5-diketone, Rhocya reaction, (5-amino-1,2 to generate 3-; 4-thiadiazoles-3 base) tonka bean camphor, then through alkaline open loop, ozone oxidation, condensation obtain SCE 2787 side-chain acid----(Z)-(5-amino-1,2 for 2-; 4-thiadiazoles-3-yl)-and 2-methoxy imino guanidine-acetic acid, this technological reaction condition is relatively harsher, and total recovery is not high.
3, Chinese patent 200910155299.7 has reported that propane dinitrile is a raw material, preparation 5-amino-1,2, the method for 4-thiadiazoles-3-acetamide derivative; Chinese patent 201010505564.2 has reported that further 4-thiadiazoles-3-acetamide derivative is a raw material with 5-amino-1,2; Preparation cephalo Toro side-chain acid: (Z)-(5-amino-1 for 2-; 2,4-thiadiazoles-3-yl)-route of 2-trityl imido grpup acetate, when wherein thiadiazoles ring 5 bit aminos are protected with benzoyl-; The selectivity of reaction is higher, but the yield of amino deprotection reaction is lower.
(3) summary of the invention
The objective of the invention is to overcome the shortcoming of prior art; The preparation method who a kind of easy and simple to handle, mild condition, good reaction selectivity are provided, yield is high, with short production cycle, " three wastes " amount is less, is easy to industrialized cephalo Lorraine side-chain acid; Will be suc as formula the 5-shown in (II) amino-1; 2,4-thiadiazoles-3-acetamide derivative and nitrous acid ester carry out oximation reaction under concentrated hydrochloric acid catalysis, in the presence of organic bases, carry out esterification with ethylization reagent then; Hydrolysis in inorganic base aqueous solution at last makes cephalo Lorraine side-chain acid.
The technical scheme that the present invention adopts is:
A kind of preparation method suc as formula (the Z)-2-shown in (I) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetate, said method comprises the steps:
(1) will be suc as formula the amino of the 5-shown in (II)-1,2,4-thiadiazoles-3-acetamide derivative, 31% combined drip C down in-30～60 ℃ in organic solvent
3～C
6Nitrous acid ester, insulation reaction 1～15 hour adds organic bases and ethylization reagent; Reacted 1～24 hour down in 0～100 ℃, suction filtration is got filter cake A; Vacuum-drying obtains suc as formula (the Z)-2-shown in (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative; Described suc as formula the 5-shown in (II) amino-1; 2, the HCl in 4-thiadiazoles-3-acetamide derivative, the aqueous hydrochloric acid, nitrous acid ester, organic bases are 1.0: 0.1～1.0: 1.0～6.0: 1.0～10.0: 1.0～10.0 with the amount of substance ratio of ethylization reagent; Described organic solvent is C
2～C
6Ester, C
1～C
6Halogenated alkane, C
2～C
6Ether or C
2～C
6The arbitrary combination of one or more in the nitrogenous organic solvent; Described ethylization reagent is monochloroethane, monobromethane, iodoethane, ethyl sulfate or diethyl carbonate; Described organic bases is triethylamine, Tri-n-Propylamine, tri-isopropyl amine, diethylammonium Tri N-Propyl Amine, tri-n-butylamine, triethylene diamine (DABCO), Tetramethyl Ethylene Diamine (TEMDA), pyridine, 2-picoline, piperidines, sodium methylate, sodium ethylate, potassium tert.-butoxide or N, the arbitrary combination of one or more in N-dimethylamino-4-pyridine (DMAP);
(2) mix with inorganic base aqueous solution suc as formula (the Z)-2-shown in (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative what step (1) obtained; 20～120 ℃ were reacted 1～24 hour down, transferred pH to 2～3 with 2～10% Hydrogen chloride, preferably transferred pH with 10% aqueous hydrochloric acid; Be cooled to 0～10 ℃ again, suction filtration is got filter cake B; Vacuum-drying obtains suc as formula (the Z)-2-shown in (I) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetate; It is described that (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1: 2～20 with the amount of substance ratio of mineral alkali suc as formula (the Z)-2-shown in (III); Described mineral alkali is one or more the arbitrary combination in Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, hydrated barta, cesium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood or the cesium carbonate;
R among formula (II), (III)
1, R
2Independent separately is C
1～C
6Alkyl.
Reaction formula of the present invention is following:
Further, the consumption of the organic solvent in the step of the present invention (1) is amino-1,2 suc as formula the 5-shown in (II), 1～20 times of 4-thiadiazoles-3-acetamide derivative quality.
Organic solvent in the preferred step of the present invention (1) is one or more the arbitrary combination in ETHYLE ACETATE, methylene dichloride, THF or the acetonitrile.
Ethylization reagent in the preferred step of the present invention (1) is monobromethane or ethyl sulfate.
Organic bases in the preferred step of the present invention (1) is one or more the arbitrary combination in triethylamine, pyridine or the sodium methylate.
Mineral alkali in the preferred step (2) of the present invention is a kind of in sodium hydroxide or the Pottasium Hydroxide or their mixing.
In the preferred step of the present invention (1) suc as formula the 5-shown in (II) amino-1; 2, HCl, nitrous acid ester, organic bases are 1.0: 0.2～0.5: 1.5～3.0: 1.5～4.0: 1.0～5.0 with the amount of substance ratio of ethylization reagent in 4-thiadiazoles-3-acetamide derivative, the aqueous hydrochloric acid.
The mass concentration of the mineral alkali in the preferred step of the present invention (2) is 0.5～25%, is preferably 8～15%.
R among the preferred formula of the present invention (II), (III)
1Be tertiary amyl, R
2Be methyl.
The preferred C of the present invention
3～C
6Nitrous acid ester be nitrous acid isopropyl ester.
Preferably (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1: 3～15 with the amount of substance ratio of mineral alkali suc as formula (the Z)-2-shown in (III) in the present invention.
Particularly, the method for the present invention's recommendation is carried out according to following steps:
(1) will be suc as formula the amino of the 5-shown in (II)-1,2,4-thiadiazoles-3-acetamide derivative, 31% mixed in hydrochloric acid are in organic solvent; Drip nitrous acid isopropyl ester, insulation reaction 1～15 hour, adding organic bases and ethylization reagent down in-20～20 ℃; Reacted 1～24 hour down in 20～40 ℃, suction filtration is got filter cake A; Vacuum-drying obtains suc as formula (the Z)-2-shown in (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative; Described suc as formula the 5-shown in (II) amino-1; 2, the HCl in 4-thiadiazoles-3-acetamide derivative, the aqueous hydrochloric acid, nitrous acid isopropyl ester, organic bases are 1.0: 0.2～0.5: 1.5～3.0: 1.5～4.0: 1.0～5.0 with the amount of substance ratio of ethylization reagent; Described organic solvent is one or more the arbitrary combination in ETHYLE ACETATE, methylene dichloride, THF or the acetonitrile; Described ethylization reagent is monobromethane or ethyl sulfate; Described organic bases is one or more the arbitrary combination in triethylamine, pyridine or the sodium methylate;
What (2) step (1) is obtained is that 8～15% inorganic base aqueous solution mixes suc as formula (the Z)-2-shown in (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative and mass concentration; 60～90 ℃ were reacted 1～24 hour down, transferred pH to 2～3 with 10% Hydrogen chloride, were cooled to 5 ℃; Suction filtration is got filter cake B, and vacuum-drying obtains (the 5-amino-1 suc as formula (the Z)-2-shown in (I); 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetate; It is described that (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1: 3～15 with the amount of substance ratio of mineral alkali suc as formula (the Z)-2-shown in (III); Described mineral alkali is a kind of in sodium hydroxide or the Pottasium Hydroxide or their mixing;
R among formula (II), (III)
1Be tertiary amyl, R
2Be methyl.
Compared with prior art, beneficial effect of the present invention is embodied in:
A) invent a novel method for preparing cephalo Lorraine side-chain acid, had originality;
The stereoselectivity of b) reacting in the route of the present invention is high, and midbody need not to make with extra care after simple separation, promptly can be used for hydrolysis reaction, obtains cephalo Lorraine side-chain acid with high yield, product HPLC content >=99.5%, trans body burden＜0.5%;
C) avoid the use of poisonous and harmful reagent such as POCl3, bromine from the source, " three wastes " amount is less;
D) raw material be easy to get, easy and simple to handle, reaction conditions is gentle, solid chooses, yield is high, " three wastes " amount is less, has bigger implementary value and economic results in society.
(4) description of drawings
Fig. 1 is that the embodiment of the invention 1 obtains (Z)-5-pivaloyl amido-1,2, and 4-thiadiazoles-3-be (1-ethoxy imino-ethanoyl-N-ethanamide
1H-NMR.
Fig. 2 is cephalo Lorraine side-chain acid that the embodiment of the invention 1 obtains
1H-NMR.
(5) specific embodiment
Below with specific embodiment technical scheme of the present invention is described, but protection scope of the present invention is not limited thereto.
(the Z)-5-pivaloyl amido-1,2 that obtains among the embodiment 1-10, (the hydrogen spectrogram spectrum of 1-ethoxy imino-ethanoyl-N-ethanamide and cephalo Lorraine side-chain acid is identical to 4-thiadiazoles-3-.
Synthesizing of cephalo Lorraine side-chain acid (Z)-2-(5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetate (I)
Embodiment 1:
(1) in the 500mL there-necked flask, with 5-pivaloyl amido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (2.1g 0.0176mol) is mixed in the THF (150g) ,-15 ℃ drip down nitrous acid isopropyl ester (46g, 0.528mol); After the insulation reaction 5 hours, and the adding triethylamine (177g, 1.760mol), 0 ℃ of following dripping bromine ethane (152g; 1.41mol), insulation reaction is after 5 hours, and suction filtration is got filter cake; Vacuum-drying obtains (Z)-5-pivaloyl amido-1,2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide) 42.0g, thick product yield 70%; White solid, fusing point: 182.0-184.2 ℃.
1H-NMR(DMSO，400MHz)：δ(ppm)1.26(3H，t，J＝8.0Hz，OCH
2CH
3)，1.28(9H，s，C(CH
3)
3)，2.24(3H，s，COCH
3)，4.29(2H，q，J?7.0Hz，OCH
2CH
3)，10.94(H，s，1H，NH-C＝N)，12.94(1H，s，J＝11.2Hz，NHCOCH
3)。
(2) (1968g 0.246mol) is mixed in the 3L bottle, and 20 ℃ of following insulation reaction 20h are cooled to 5 ℃ with 0.5%NaOH solution with the thick product 42.0g (0.123mol) of step (1) gained; Transfer system pH to 2～3 with 2% Hydrogen chloride then, suction filtration is got filter cake and is obtained cephalo Lorraine side-chain acid 18.6g, with 5-pivaloyl amido-1; 2,4-thiadiazoles-3-ethanoyl-N-ethanamide calculates, and total recovery is 49%; White solid, fusing point: 176.2～177.5 ℃, HPLC purity is 99.5%.
1H?NMR(400MHz，DMSO-d
6)δ1.19(3H，t，J＝8.0Hz，CH
3，)，4.18(2H，q，J＝8.0Hz，CH
2，)，8.06(2H，br?s，NH
2)。
Embodiment 2:
(1) in the 2L there-necked flask, with 5-pivaloyl amido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (20.7g 0.176mol) is mixed in the methylene dichloride (1000mL) ,-30 ℃ drip down nitrous acid isopropyl ester (76.0g, 0.88mol); After the insulation reaction 10 hours, and the adding Tri-n-Propylamine (20.2g, 0.176mol), 0 ℃ of following dripping bromine ethane (152g; 1.41mol), insulation reaction is after 10 hours, and suction filtration is got filter cake; Get 36g bullion (Z)-5-pivaloyl amido-1,2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide), thick product yield 60%; White solid, fusing point: 181.3-183.5 ℃.
(2) (470.4g 0.21mol) is mixed in the 1L bottle, 90 ℃ of following insulation reaction 20h with step (1) gained bullion 36g (0.105mol) and 2.5%KOH solution; Be cooled to 5 ℃, transfer pH to 2～3, suction filtration with 5% Hydrogen chloride; Get filter cake and get cephalo Lorraine side-chain acid 13.3g, total recovery is 35%, white solid; Fusing point: 176.5～177.6 ℃, HPLC purity is 99.6%.
Embodiment 3:
(1) in the 1L there-necked flask, with 5-pivaloyl amido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (10.4g 0.088mol) is mixed in the acetonitrile (50g), 0 ℃ drip down nitrous acid isopropyl ester (92.0g, 1.05mol); After the insulation reaction 15 hours, and the adding pyridine (69.5g, 0.88mol), 40 ℃ drip ethyl sulfate (27g down; 0.176mol), insulation reaction is after 1 hour, and suction filtration is got filter cake; Get 39g bullion (Z)-5-pivaloyl amido-1,2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide), thick product yield 65%; White solid, fusing point: 182.4-183.2 ℃.
(2) (1949g 0.57mol) is mixed in the 3L bottle, 100 ℃ of following insulation reaction 24h with step (1) gained bullion 39g (0.114mol) and 5%Ba (OH) 2 solution; Be cooled to 5 ℃, transfer pH to 2～3, suction filtration with 10% Hydrogen chloride; Get filter cake and get cephalo Lorraine side-chain acid 19.8g, total recovery is 52%, white solid; Fusing point: 177.3～178.1 ℃, HPLC purity is 98.5%.
Embodiment 4:
(1) in the 2L there-necked flask, with 5-pivaloyl amido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (4.12g 0.035mol) is mixed in the THF (750.0g), 60 ℃ drip down nitrous acid isopropyl ester (61.0g, 0.70mol); After the insulation reaction 1 hour, and the adding sodium methylate (28g, 0.528mol), 100 ℃ drip diethyl carbonate (207.7g down; 1.76mol), insulation reaction is after 12 hours, and suction filtration gets 43.2g bullion (Z)-5-pivaloyl amido-1; 2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide), thick product yield 72%; White solid, fusing point: 182.8-183.7 ℃.
(2) (754g 0.506mol) is mixed in the 1L there-necked flask, 110 ℃ of following insulation reaction 1h with step (1) gained bullion 43.2g (0.127mol) and 10%CsOH solution; Be cooled to 5 ℃, transfer pH to 2～3, suction filtration with 10% Hydrogen chloride; Get filter cake and get cephalo Lorraine side-chain acid 17.1g, total recovery is 45%, white solid; Fusing point: 175.8～176.8 ℃, HPLC purity is 99.3%.
Embodiment 5:
(1) in the 500mL there-necked flask, with 5-acetamido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (6.2g 0.053mol) is mixed in the ETHYLE ACETATE (250.0g), 10 ℃ drip down nitrous acid isopropyl ester (15.3g, 0.176mol); After the insulation reaction 4 hours, and the adding triethylamine (76.7g, 0.76mol), 60 ℃ of following dripping bromine ethane (102g; 0.95mol), insulation reaction is after 24 hours, and suction filtration obtains the thick product of 31.7g (Z)-5-pivaloyl amido-1; 2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide), thick product yield 60%; White solid, fusing point: 183.3-184.4 ℃.
(2) (133.5g 0.46mol) is mixed in the 1L there-necked flask, 60 ℃ of following insulation reaction 10h with step (1) gained bullion 31.7g (0.093mol) and 8%LiOH solution; Be cooled to 5 ℃, transfer pH to 2～3, suction filtration with 4% Hydrogen chloride; Get cephalo Lorraine side-chain acid 18.9g, total recovery is 45%, white solid; Fusing point: 176.5～177.8 ℃, HPLC purity is 98.4%.
Embodiment 6:
(1) in the 500mL there-necked flask, with 5-pivaloyl amido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (4.1g 0.035mol) is mixed in (250g) in the THF, 20 ℃ drip down nitrous acid isopropyl ester (67.6g, 0.76mol); After the insulation reaction 7 hours, and the adding triethylamine (38.0g, 0.38mol), 25 ℃ of following dripping bromine ethane (133g; 1.23mol), insulation reaction is after 15 hours, and suction filtration gets the thick product of 38g (Z)-5-pivaloyl amido-1; 2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide) (III), thick product yield 63%; White solid, fusing point: 182.3-183.7 ℃.
(2) with step (1) gained bullion 38g (0.111mol) and 25%Na
2CO
3(944g 2.23mol) is mixed in the 1L there-necked flask solution, and 70 ℃ of following insulation reaction 15h are cooled to 5 ℃; Transfer PH to 2～3 with 5% Hydrogen chloride, suction filtration gets cephalo Lorraine side-chain acid 12.2g, and total recovery is 32%; White solid, fusing point: 175.8～176.9 ℃, HPLC purity is 99.5%.
Embodiment 7:
(1) in the 2L there-necked flask, with 5-acetamido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (1.78g 0.0152mol) is mixed in the 500g methylene dichloride, 5 ℃ drip down nitrous acid isopropyl ester (84.0g, 0.95mol); After the insulation reaction 6 hours, and the adding triethylamine (153g, 1.52mol), 10 ℃ drip iodoethane (30.2g down; 0.19mol), insulation reaction is after 8 hours, and suction filtration obtains the thick product of 32.2g (Z)-5-pivaloyl amido-1; 2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide), thick product yield 61%; White solid, fusing point: 182.8-184.3 ℃.
(2) with step (1) gained bullion 32.3g (0.095mol) and 25%K
2CO
3(1041g 1.89mol) mixes solution, and 120 ℃ of following insulation reaction 18h are cooled to 5 ℃; Transfer pH to 2～3 with 10% Hydrogen chloride, suction filtration gets cephalo Lorraine side-chain acid 7.98g, and total recovery is 21%; White solid, fusing point: 177.5～178.6 ℃, HPLC purity is 99.6%.
Embodiment 8
(1) in the 500mL there-necked flask, with 5-pivaloyl amido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (4.12g 0.035mol) is mixed in the acetonitrile (300g) ,-20 ℃ drip down nitrous acid straight butyl (54.4g, 0.528mol); After the insulation reaction 3 hours, and the adding triethylamine (26.6g, 0.264mol), 30 ℃ of following dripping bromine ethane (95g; 0.88mol), insulation reaction is after 3 hours, and suction filtration is got filter cake; Vacuum-drying obtains 43.2g (Z)-5-pivaloyl amido-1,2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide), thick product yield 72%; White solid, fusing point: 183.2-184.5 ℃.
(2) (759g 0.38mol) is mixed in the 1L bottle, 80 ℃ of following insulation reaction 10h with 2%NaOH solution with the thick product 43.2g (0.127mol) of step (1) gained; Be cooled to 5 ℃, transfer system pH to 2～3, suction filtration with 8% Hydrogen chloride then; Get filter cake and obtain cephalo Lorraine side-chain acid 25.8g, total recovery is 68%, white solid; Fusing point: 177.4～178.5 ℃, HPLC purity is 99.1%.
(1) in the 1000mL there-necked flask, with 5-pivaloyl amido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (10.3g 0.088mol) is mixed in the THF (600g), 20 ℃ drip down Isopentyl nitrite (30.8g, 0.264mol); After the insulation reaction 5 hours, and the adding triethylamine (71.1g, 0.704mol), 20 ℃ of following dripping bromine ethane (19g; 0.176mol), insulation reaction is after 5 hours, and suction filtration is got filter cake; Vacuum-drying obtains 45g (Z)-5-pivaloyl amido-1,2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide), thick product yield 75%; White solid, fusing point: 184.0-184.5 ℃.
(2) (316g 1.98mol) is mixed in the 1L there-necked flask, 60 ℃ of following insulation reaction 15h with 25%NaOH solution with the thick product 45g (0.132mol) of step (1) gained; Be cooled to 5 ℃, transfer system pH to 2～3, suction filtration with 4% Hydrogen chloride then; Get filter cake and obtain cephalo Lorraine side-chain acid 25.8g, total recovery is 68%, white solid; Fusing point: 176.5～177.9 ℃, HPLC purity is 98.6%.
(1) in the 500mL there-necked flask, with 5-pivaloyl amido-1,2,4-thiadiazoles-3-ethanoyl-N-ethanamide (50.0g; 0.176mol), 31% aqueous hydrochloric acid (6.2g 0.0528mol) is mixed in the acetonitrile (350g), 0 ℃ drip down the just own ester of nitrous acid (46.1g, 0.352mol); After the insulation reaction 8 hours, and the adding triethylamine (53.3g, 0.528mol), 40 ℃ of following dripping bromine ethane (47.5g; 0.44mol), insulation reaction is after 7 hours, and suction filtration is got filter cake; Vacuum-drying obtains 40.2g (Z)-5-pivaloyl amido-1,2,4-thiadiazoles-3-(1-ethoxy imino-ethanoyl-N-ethanamide), thick product yield 67%; White solid, fusing point: 182.0-183.5 ℃.
(2) (824g 1.18mol) is mixed in the 1L bottle, and 90 ℃ of following insulation reaction 8h are cooled to 5 ℃ with 8%KOH solution with the thick product 40.2g (0.118mol) of step (1) gained; Transfer system pH to 2～3 with 3% Hydrogen chloride then, suction filtration is got filter cake and is obtained cephalo Lorraine side-chain acid 25.8g, with 5-pivaloyl amido-1; 2,4-thiadiazoles-3-ethanoyl-N-ethanamide calculates, and total recovery is 68%; White solid, fusing point: 177.8～178.4 ℃, HPLC purity is 98.4%.
Claims (9)
1. the preparation method suc as formula (the Z)-2-shown in (I) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetate is characterized in that said method comprises the steps:
(1) will be suc as formula the amino of the 5-shown in (II)-1,2,4-thiadiazoles-3-acetamide derivative, 31% combined drip C down in-30～60 ℃ in organic solvent
3～C
6Nitrous acid ester, insulation reaction 1～15 hour adds organic bases and ethylization reagent; Reacted 1～24 hour down in 0～100 ℃, suction filtration is got filter cake A; Vacuum-drying obtains suc as formula (the Z)-2-shown in (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative; Described suc as formula the 5-shown in (II) amino-1; 2, the HCl in 4-thiadiazoles-3-acetamide derivative, the aqueous hydrochloric acid, nitrous acid ester, organic bases are 1.0: 0.1～1.0: 1.0～6.0: 1.0～10.0: 1.0～10.0 with the amount of substance ratio of ethylization reagent; Described organic solvent is C
2～C
6Ester, C
1～C
6Halogenated alkane, C
2～C
6Ether or C
2～C
6The arbitrary combination of one or more in the nitrogenous organic solvent; Described ethylization reagent is monochloroethane, monobromethane, iodoethane, ethyl sulfate or diethyl carbonate; Described organic bases is triethylamine, Tri-n-Propylamine, tri-isopropyl amine, diethylammonium Tri N-Propyl Amine, tri-n-butylamine, triethylene diamine, Tetramethyl Ethylene Diamine, pyridine, 2-picoline, piperidines, sodium methylate, sodium ethylate, potassium tert.-butoxide or N, the arbitrary combination of one or more in N-dimethylamino-4-pyridine;
(2) mix with inorganic base aqueous solution suc as formula (the Z)-2-shown in (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative what step (1) obtained; 20～120 ℃ were reacted 1～24 hour down, transferred pH to 2～3 with 2～10% diluted hydrochloric acid aqueous solutions, were cooled to 0～10 ℃; Suction filtration is got filter cake B, and vacuum-drying obtains (the 5-amino-1 suc as formula (the Z)-2-shown in (I); 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetate; It is described that (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1: 2～20 with the amount of substance ratio of mineral alkali suc as formula (the Z)-2-shown in (III); Described mineral alkali is one or more the arbitrary combination in Lithium Hydroxide MonoHydrate, sodium hydroxide, Pottasium Hydroxide, hydrated barta, cesium hydroxide, Quilonum Retard, yellow soda ash, salt of wormwood or the cesium carbonate;
R among formula (II), (III)
1, R
2Independent separately is C
1～C
6Alkyl.
2. preparation method as claimed in claim 1, the consumption that it is characterized in that the organic solvent in the described step (1) is for amino-1,2 suc as formula the 5-shown in (II), 1～20 times of 4-thiadiazoles-3-acetamide derivative quality.
3. the method for claim 1 is characterized in that organic solvent in the described step (1) is one or more the arbitrary combination in ETHYLE ACETATE, methylene dichloride, THF or the acetonitrile.
4. as requiring 1 described method in the right, it is characterized in that the ethylization reagent in the described step (1) is monobromethane or ethyl sulfate.
5. the method for claim 1 is characterized in that organic bases in the said step (1) is one or more the arbitrary combination in triethylamine, pyridine or the sodium methylate.
6. the method for claim 1 is characterized in that mineral alkali in the described step (2) is a kind of in sodium hydroxide or the Pottasium Hydroxide or their mixing.
7. the method for claim 1; It is characterized in that in the said step (1) suc as formula the 5-shown in (II) amino-1; 2, the HCl in 4-thiadiazoles-3-acetamide derivative, the aqueous hydrochloric acid, nitrous acid ester, organic bases are 1.0: 0.2～0.5: 1.5～3.0: 1.5～4.0: 1.0～5.0 with the amount of substance ratio of ethylization reagent.
8. the method for claim 1, the mass concentration that it is characterized in that the mineral alkali in the described step (2) is 0.5～25%.
9. the method for claim 1 is characterized in that described method carries out according to following steps:
(1) will be suc as formula the amino of the 5-shown in (II)-1,2,4-thiadiazoles-3-acetamide derivative, concentrated hydrochloric acid are mixed in the organic solvent; Drip nitrous acid isopropyl ester, insulation reaction 1～15 hour, adding organic bases and ethylization reagent down in-20～20 ℃; Reacted 1～24 hour down in 20～40 ℃, suction filtration is got filter cake A and is obtained (the 5-amino-1 suc as formula (the Z)-2-shown in (III); 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative; Described suc as formula the 5-shown in (II) amino-1; 2, the HCl in 4-thiadiazoles-3-acetamide derivative, the aqueous hydrochloric acid, nitrous acid isopropyl ester, organic bases are 1.0: 0.2～0.5: 1.5～3.0: 1.5～4.0: 1.0～5.0 with the amount of substance ratio of ethylization reagent; Described organic solvent is one or more the arbitrary combination in ETHYLE ACETATE, methylene dichloride, THF or the acetonitrile; Described ethylization reagent is monobromethane or ethyl sulfate; Described organic bases is one or more the arbitrary combination in triethylamine, pyridine or the sodium methylate;
What (2) step (1) is obtained is that 8～15% inorganic base aqueous solution mixes suc as formula (the Z)-2-shown in (III) (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative and mass concentration; 60～90 ℃ were reacted 1～24 hour down, transferred pH to 2～3 with 10% Hydrogen chloride, were cooled to 5 ℃; Suction filtration is got filter cake B, and vacuum-drying obtains (the 5-amino-1 suc as formula (the Z)-2-shown in (I); 2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetate; It is described that (5-amino-1,2,4-thiadiazoles-3-yl)-2-ethoxy imido grpup acetamide derivative is 1: 3～15 with the amount of substance ratio of mineral alkali suc as formula (the Z)-2-shown in (III); Described mineral alkali is a kind of in sodium hydroxide or the Pottasium Hydroxide or their mixing; R among formula (II), (III)
1Be tertiary amyl, R
2Be methyl.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103396380A (en) * | 2013-06-07 | 2013-11-20 | 浙江工业大学 | Preparation method of (E)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic aid |
| CN104031040A (en) * | 2014-06-05 | 2014-09-10 | 济南诚汇双达化工有限公司 | Synthesis method of 2-sulfydryl-4-pyridyl thiazole |
| CN107621512A (en) * | 2017-11-02 | 2018-01-23 | 北京满格医药科技有限公司 | A kind of method of pre-column derivatization method measure CPT ester side chain acyl chlorides purity |
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| CN101987837A (en) * | 2010-01-12 | 2011-03-23 | 石家庄康美泰医药科技有限公司 | Preparation method of 1,2,4-thiadiazole oximido acetic acid compound |
| CN102127034A (en) * | 2010-12-29 | 2011-07-20 | 蚌埠丰原医药科技发展有限公司 | Preparation method of cefozopran side chain acid |
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| CN101987837A (en) * | 2010-01-12 | 2011-03-23 | 石家庄康美泰医药科技有限公司 | Preparation method of 1,2,4-thiadiazole oximido acetic acid compound |
| CN102127034A (en) * | 2010-12-29 | 2011-07-20 | 蚌埠丰原医药科技发展有限公司 | Preparation method of cefozopran side chain acid |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103396380A (en) * | 2013-06-07 | 2013-11-20 | 浙江工业大学 | Preparation method of (E)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic aid |
| CN104031040A (en) * | 2014-06-05 | 2014-09-10 | 济南诚汇双达化工有限公司 | Synthesis method of 2-sulfydryl-4-pyridyl thiazole |
| CN104031040B (en) * | 2014-06-05 | 2016-09-14 | 山东诚汇双达药业有限公司 | The synthetic method of 2-sulfydryl-4-pyridyl thiazole |
| CN107621512A (en) * | 2017-11-02 | 2018-01-23 | 北京满格医药科技有限公司 | A kind of method of pre-column derivatization method measure CPT ester side chain acyl chlorides purity |
| CN107621512B (en) * | 2017-11-02 | 2020-07-31 | 扬子江药业集团有限公司 | Method for determining purity of cefaclor side chain acyl chloride by pre-column derivatization method |
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