CN109134508A - A kind of preparation method of the high yield high quality cefotiam hydrochloride suitable for industrialized production - Google Patents
A kind of preparation method of the high yield high quality cefotiam hydrochloride suitable for industrialized production Download PDFInfo
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- CN109134508A CN109134508A CN201810906436.5A CN201810906436A CN109134508A CN 109134508 A CN109134508 A CN 109134508A CN 201810906436 A CN201810906436 A CN 201810906436A CN 109134508 A CN109134508 A CN 109134508A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/36—Methylene radicals, substituted by sulfur atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
- C07D501/06—Acylation of 7-aminocephalosporanic acid
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
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- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The present invention relates to a kind of preparation methods of high yield high quality cefotiam hydrochloride suitable for industrialized production, the following steps are included: (1) is using methylene chloride as solvent, using one kettle way, ATAHCl and mesyl chloride generate intermediate 1 in the form of acid anhydrides, and then the acid anhydrides feed liquid directly reacts generation intermediate 2 with 7-amino-cephalosporanic acid (7-ACA) under organic base catalytic；(2) using acetonitrile as solvent, intermediate 2 and 1- (2- decil) -5- sulfydryl -1,2,3, tetra- ammonia azoles (DMMT) of 4- react in the presence of boron trifluoride acetonitrile complex compound, cefotiam hydrochloride crude product is obtained, then by being refining to obtain cefotiam hydrochloride.Synthetic intermediate 1 and intermediate 2 of the present invention, cefotiam hydrochloride crude product and cefotiam hydrochloride fine work use single solvent when preparing respectively, are convenient for recovery；Step operation is easy, and conversion rate of products is high, and impurity is small, and production cost is low, the cefotiam hydrochloride suitable for industrialized production high quality.
Description
Technical field
The present invention relates to a kind of preparation methods of high yield high quality cefotiam hydrochloride suitable for industrialized production, belong to
Chemicals synthesis technical field.
Background technique
Cefotiam hydrochloride (cefotiam Hydrochloride) is semi-synthetic second generation cephalosporin.It is blue to leather
The effect of family name's positive bacteria is hard to tell which is better with first generation cephalosporins medicine, and to the antibacterial range of Gram-negative bacteria than the first generation
Cephalosporins medicine mechanism of action is good, the effects of to haemophilus influenzae, Escherichia coli, Klebsiella, proteus mirabilis compared with
By force, also there is antibacterial action to enterobacteria, citrobacter, indole-positive proteus etc..
Entitled (6R, the 7R) -7- [[(2- amino -4- thiophene of cefotiam hydrochloride (cefotiam Hydrochloride) chemistry
Oxazolyl) acetyl group] amino] -3- [[1- [2- (dimethylamino) ethyl] -1H-TETRAZOLE -5- base] sulphomethyl] -8- oxo -5- sulphur
Miscellaneous -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid dihydrochloride, molecular formula C18H23N9O4S3.2HCl, molecular weight is
598.55, structural formula is as follows:
The main preparation methods of cefotiam hydrochloride have at present:
Chinese patent document CN102850381A discloses a kind of preparation method of cefotiam hydrochloride crude product, with ATA-
HCl and vilsmeier reagent is that raw material prepares ATC-HCl, then in alkaline aqueous organic solvent, 7-DMT and ATC-HCl
After secondary filter, acetone is added in reaction, and growing the grain obtains Cefotiam crude product.But the ATC-HCl yield of this method preparation is inclined
It is low, it is prepared using 7-DMT as starting material relatively low for peace crude product purity and yield.
Chinese patent document CN102898441A discloses a kind of synthetic method of Cefotiam, with acetonitrile, 7- amino head
Spore alkanoic acid and 1- (2- dimethyl aminoethyl) -1H-5- sulfydryl-tetrazole are raw material, react and 7- amino -3- [1- (2- bis- is made
Methylaminoethyl) -1H- tetrazole -5- base) sulfidomethyl] cephalosporanic acid dihydrochloride；The product and purified water and isopropanol are anti-
It answers rear decoloring to obtain 7-amino-cephalosporanic acid and 1- (2- dimethyl aminoethyl) -1H-5- sulfydryl-tetrazole as raw material, reacts
7- amino -3- [1- (2- dimethyl aminoethyl) -1H- tetrazole -5- base) sulfidomethyl] cephalosporanic acid dihydrochloride is made；So
The compound is by processing to obtain formyl Cefotiam afterwards；Formyl Cefotiam reacts generation with isopropanol, purified water, hydrochloric acid again
Cefotiam crude product finally obtains Cefotiam crude product by secondary refining, and last secondary refining obtains Cefotiam finished product.But
It is that this method step is comparatively laborious, and yield is low.
Chinese patent document CN101045733A discloses a kind of spore for peace hydrochloric acid salt production process, including by ATA raw material
It is passed through dry hydrogen chloride gas after solvent is added, chlorinating agent is then added, temperature is 0~30 DEG C, is filtered out after reaction
ATC.HCl crystallization；By 7-ACMT plus alkali soluble in aqueous solvent, ATC.HCl acylation reaction, temperature -10~35 DEG C, reaction is added
End separates organic solvent, and hydrochloric acid is added in water phase, and hydrophilic solvent is added, and cefotiam chloride crystallization is precipitated.But it should
The method operation that method prepares ATC.HCl is more complicated, and controllability is not strong；Mixed solvent, environmental protection are used when synthesis is for peace crude product
Pressure is larger, and obtained crude yield is relatively low.
Chinese patent document CN103910749A discloses a kind of preparation method of cefotiam hydrochloride, using ATA as raw material,
FATAA is activated to obtain by formylated, at mixed anhydride, FCEFO is then docked to obtain with 7-ACMT, object is made in last piptonychia acyl ---
Cefotiam hydrochloride (CEFO).But this method complex steps, whole yield are relatively low.
Chinese patent document CN101633666A discloses a kind of cefotiam hydrochloride compound, including by 2- amino thiophene
Azoles -4- acetic acid is reacted with formic acid, is generated 2- formamido group thiazole -4- acetic acid, is added 7-ACMT and triethylamine, with N, N- bis- is different
Propylethylamine and dimethylformamide are that solvent is stirred to react using paratoluensulfonyl chloride as catalyst, add hydrochloric acid, are made
Cefotiam hydrochloride.But this method solvent, using complexity, environmental protection pressure is big.
Therefore, the preparation method for finding a kind of high yield high quality cefotiam hydrochloride suitable for industrialized production, becomes
This field technical problem urgently to be resolved.For this purpose, proposing the present invention.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of salt of the high yield high quality of suitable scale industrial production
The preparation method of sour Cefotiam.This method is using methylene chloride as solvent, using one kettle way, ATAAHCl and mesyl chloride with
The form of acid anhydrides generates intermediate 1, then under organic base catalytic the acid anhydrides feed liquid directly with 7-amino-cephalosporanic acid (7-ACA)
Reaction generates intermediate 2；Using acetonitrile as solvent, intermediate 2 and 1- (2- decil) -5- sulfydryl -1,2,3, tetra- ammonia azoles of 4-
(DMMT) it is reacted in the presence of boron trifluoride acetonitrile complex compound, obtains cefotiam hydrochloride crude product, then is high-purity by being refining to obtain
The cefotiam hydrochloride of degree.Synthetic intermediate 1 and intermediate 2 in the method for the present invention, cefotiam hydrochloride crude product and hydrochloric acid cephalo
Single solvent is used respectively when for peace fine work preparation, is convenient for recovery；The synthetic method step operation is easy, conversion rate of products
Height, impurity is small, and production cost is low, the cefotiam hydrochloride suitable for industrialized production high quality.
Term explanation:
Unless otherwise instructed, 7-ACA, DMMT, ATAA.HCl, intermediate 2 and intermediate 1 is previously mentioned in the present invention to refer in particular to
Corresponding compound in term explanation, reference relationship having the same.
7-amino-cephalosporanic acid (7-ACA) chemical structural formula is as follows:
1- (2- decil) -5- sulfydryl -1,2,3,4- tetra- ammonia azoles (DMMT) chemical structural formula it is as follows:
2 chemical structural formula of intermediate is as follows:
Aminothiazole acid hydrochloride (ATAA.HCl) chemical structural formula is as follows:
1 chemical structural formula of intermediate is as follows:
Technical scheme is as follows:
A kind of synthetic method of the cefotiam hydrochloride of high yield high quality, includes the following steps:
(1) using methylene chloride as solvent, using one kettle way, mesyl chloride is reacted with ATAAHCl generates intermediate 1,7-
Under organic base catalytic, reaction generates intermediate 2 for ACA and 1 feed liquid of intermediate；
(2) using acetonitrile as solvent, in the presence of boron trifluoride acetonitrile complex compound, intermediate 2 is reacted with DMMT generates hydrochloric acid head
Spore is for peace crude product；
(3) after the dissolution of cefotiam hydrochloride crude product, recrystallisation solvent crystallization is added after active carbon filters, obtains high in high yield
The cefotiam hydrochloride of quality.
Preferred according to the present invention, the reaction dissolvent of intermediate 1 is methylene chloride in the step (1)；
Preferably, the molar ratio of mesyl chloride and ATAAHCl are (1.1-1.2): 1；
Preferably, it is -20-0 DEG C that mesyl chloride, which reacts the reaction temperature of synthetic intermediate 1 with ATAAHCl, the reaction time
For 1-2h.
Preferred according to the present invention, organic base described in the step (1) is diisopropylamine, diethylamine or triethylamine；
Preferably, the molar ratio of organic base and 7-ACA are (1.2-1.5): 1；
Preferably, the reaction temperature that 7-ACA and the reaction of intermediate 1 generate intermediate 2 is -5-5 DEG C, reaction time 1-
2h。
It is preferred according to the present invention, after reaction generates intermediate 2 in the step (1), using methylene chloride as recrystallisation solvent,
Regulation system pH=5.0-7.0 obtains intermediate 2.
Preferred according to the present invention, intermediate 2 and DMMT molar ratio are 1:(1.0-1.2 in the step (2)).
Preferred according to the present invention, reaction temperature is 0~30 DEG C in the step (2), reaction time 2-3h.
It is preferred according to the present invention, the molar ratio (2- of boron trifluoride acetonitrile complex compound and intermediate 2 in the step (2)
3): 1.
Preferred according to the present invention, recrystallisation solvent described in the step (3) is acetone.
The synthesis route of the method for the invention is as follows:
Beneficial effect
1, preparation method of the present invention, easy to operate, reaction step is few, be suitable for industrialized production；
2, preparation method of the present invention, intermediate 1 and 2 synthetic reaction of intermediate use dichloromethane easy to recovery of applied
Alkane is good for the environment, and reduces production cost and environmental protection expenditure；
3, preparation method of the present invention, the synthesis of cefotiam hydrochloride crude product use single solvent acetonitrile, easily recycle
It applies, reduces production cost and environmental protection expenditure, 7-ACA to 92% or more cefotiam hydrochloride crude product reaction conversion ratio；
4, preparation method of the invention, dissolution solvent and recrystallisation solvent when purification are same solvent, recrystallisation solvent with it is molten
Solution solvent is compared, and in low ratio for dissolving, ratio is increased to a certain degree, then product crystallization is precipitated；
5, preparation method of the present invention, the cefotiam hydrochloride purity being refining to obtain is 99.7% or more, solution face
Color has unexpectedly reached colourless rank.
Detailed description of the invention
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram for the product that embodiment 3 obtains.
Fig. 2 is the carbon-13 nmr spectra figure for the product that embodiment 3 obtains.
Specific embodiment
Below by embodiment, technical scheme is described further, but provided embodiment should not be by
It is interpreted as being construed as limiting the scope of the present invention.
The preparation of embodiment 1 cefotiam hydrochloride side chain (intermediate 1) and cefotiam hydrochloride intermediate 2
A: putting into methylene chloride 200ml in reaction flask, and 7-ACA 45g is added, 0~5 DEG C of temperature control, tetramethylguanidine is added dropwise
21ml, stirring.
B: putting into methylene chloride 300ml in reaction flask, and ATAAHCl 36g is added, and methylsulphur is added dropwise in temperature control -20~0 DEG C
Acyl chlorides 25.4g adds then dropwise addition diisopropylamine (DIPA) 35g, temperature -20~0 DEG C is maintained to react 1h, and reaction terminates, obtains
Cefotiam hydrochloride side chain (intermediate 1) A is added in B, temperature control -5~5 DEG C, insulation reaction 1h, end of reaction, is added
200ml washing, layering discard water phase, 0~5 DEG C of organic phase temperature control, methylene chloride 30ml/DIPA 17g mixed liquor are added dropwise and adjusts
System pH=5.0~7.0, drop finish, growing the grain 1h, filtering, and 100ml methylene chloride is washed, and obtain the about 66g of intermediate 2, yield 93%.
The preparation of 2 cefotiam hydrochloride crude product of embodiment
Acetonitrile 200ml is put into reaction flask, 0~25 DEG C of temperature control, boron trifluoride is added in intermediate 2 66g, DMMT 28g
Acetonitrile complex compound 74g, reacts 2h by 0~30 DEG C of temperature control, and reaction terminates, and the sodium pyrosulfite that 40ml 2% is added dropwise into feed liquid is molten
Liquid terminates reaction, and 0~30 DEG C of temperature control, concentrated hydrochloric acid 28ml is added, and acetonitrile 400ml crystallization is added dropwise.Filtering, the washing of 200ml acetonitrile, 35
~40 DEG C of vacuum drying, moisture≤7.0% obtain cefotiam hydrochloride crude product 87.5g, 7-ACA to cefotiam hydrochloride crude product
Yield about 92%, purity 99.2%, maximum contaminant 0.18%.
The preparation of 3 cefotiam hydrochloride fine work of embodiment
Water 50ml, acetone 50ml are put into reaction flask, 0~25 DEG C of temperature control, put into the cefotiam hydrochloride that embodiment 2 obtains
Pacify crude product 30g, after stirring and dissolving, be added acetone 50ml, active carbon 1.5g, decolorization filtering, 10ml water/20ml acetone displacement adds
Entering acetone 400ml, drop finishes, filters after 0~10 DEG C of growing the grain 1h of temperature control, acetone washing, 30~40 DEG C of vacuum drying, moisture≤
7.0%, obtain cefotiam hydrochloride fine work about 28.5g, yield 98%, purity 99.7%, maximum nonspecific impurity 0.02%.
The nuclear magnetic resonance spectroscopy for the product that the present embodiment obtains is as shown in Figure 1, carbon-13 nmr spectra is as shown in Figure 2.
1H-NMR (400MHz, DMSO-d6): δ 2.83 (s, 6H), δ 3.63 (s, 2H), 3.65 (t, 2H), δ 3.69~3.80
(AB, 2H), 4.28~4.37 (AB, 2H), 4.77 (t, 2H), 5.09 (d, 1H), 5.65 (dd, 1H), 6.64 (s, 1H), 9.20
(d, 1H).
Comparative example 1
In preparation route of the present invention, reaction temperature is investigated when synthetic intermediate 2, when temperature is lower than -5 DEG C, reaction speed
Slowly, yield is normal, but energy consumption is high, when temperature is higher than 5 DEG C (8~10 DEG C of experimental temperature), 2 yield 90% of intermediate, the reason is that instead
Reaction raw materials (intermediate 1) have degradation during answering.
Comparative example 2
In preparation route of the present invention, crystallization pH is investigated when synthetic intermediate 2, (experiment pH=4.0- when pH is lower than 5.0
4.5), 2 yield 87% of intermediate, the reason is that intermediate 2 is insufficient at salt, (experiment pH=when the high .pH of mother liquor being caused to be higher than 7.0
7.5.-8.0), 2 yield 91% of intermediate, the reason is that intermediate 2 has degradation to lead to yield in crystallization process under alkaline condition
It is relatively low.
Comparative example 3
In preparation route of the present invention, the dosage of boron trifluoride acetonitrile is investigated when synthetic hydrochloric acid Cefotiam crude product, trifluoro
When changing boron acetonitrile and 2 molar ratio of intermediate less than 2:1 (experimental measuring 1.5:1), reaction speed is slow, and intermediate 2 remains higher, salt
When sour Cefotiam crude yield 89%, boron trifluoride acetonitrile and 2 molar ratio of intermediate are greater than 3:1 (experimental measuring 3.5:1), receive
Rate is normal, but increased costs.
Claims (10)
1. a kind of synthetic method of the cefotiam hydrochloride of high yield high quality, includes the following steps:
(1) using methylene chloride as solvent, using one kettle way, mesyl chloride reacted with ATAAHCl generate intermediate 1,7-ACA and
For 1 feed liquid of intermediate under organic base catalytic, reaction generates intermediate 2；
(2) using acetonitrile as solvent, in the presence of boron trifluoride acetonitrile complex compound, intermediate 2 is reacted with DMMT generates cefotiam hydrochloride
Pacify crude product；
(3) after the dissolution of cefotiam hydrochloride crude product, recrystallisation solvent crystallization is added after active carbon filters, obtains high yield high quality
Cefotiam hydrochloride.
2. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that intermediate in the step (1)
The reaction dissolvent of body 1 is methylene chloride.
3. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that methylsulphur in the step (1)
The molar ratio of acyl chlorides and ATAAHCl are (1.1-1.2): 1.
4. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that methylsulphur in the step (1)
The reaction temperature that acyl chlorides reacts synthetic intermediate 1 with ATAAHCl is -20-0 DEG C, reaction time 1-2h.
5. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that step has described in (1)
Machine alkali is diisopropylamine, diethylamine or triethylamine；
Preferably, the molar ratio of organic base and 7-ACA are (1.2-1.5): 1.
6. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that 7-ACA is in step (1)
The reaction temperature that the reaction of mesosome 1 generates intermediate 2 is -5-5 DEG C, reaction time 1-2h.
7. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that intermediate in the step (2)
Body 2 and DMMT molar ratio are 1:(1.0-1.2).
8. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that reaction in the step (2)
Temperature is 0~30 DEG C, reaction time 2-3h.
9. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that trifluoro in the step (2)
The molar ratio (2-3) of change boron acetonitrile complex compound and intermediate 2: 1.
10. the synthetic method of cefotiam hydrochloride according to claim 1, which is characterized in that described in the step (3)
Recrystallisation solvent is acetone.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100144A (en) * | 2019-12-30 | 2020-05-05 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis process of cefathiamidine |
| CN111533710A (en) * | 2020-06-02 | 2020-08-14 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
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| CN104356146A (en) * | 2014-11-14 | 2015-02-18 | 浙江浙邦制药有限公司 | Method for preparing cefotiam hydrochloride |
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2018
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111100144A (en) * | 2019-12-30 | 2020-05-05 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis process of cefathiamidine |
| CN111100144B (en) * | 2019-12-30 | 2022-12-06 | 山东罗欣药业集团恒欣药业有限公司 | Synthesis process of cefathiamidine |
| CN111533710A (en) * | 2020-06-02 | 2020-08-14 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
| CN111533710B (en) * | 2020-06-02 | 2022-04-22 | 江苏恒沛药物科技有限公司 | Method for preparing cefotiam intermediate 2-aminothiazole-4-acetic acid by one-pot method |
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Application publication date: 20190104 |