* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Reference:
[1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 14, p. 1804 - 1810
2
[ 27920-90-7 ]
[ 110-94-1 ]
[ 957-68-6 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 14, p. 1804 - 1810
3
[ 28242-83-3 ]
[ 3184-35-8 ]
[ 957-68-6 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2005, vol. 347, # 14, p. 1804 - 1810
4
[ 61-24-5 ]
[ 957-68-6 ]
Reference:
[1] Journal of Organic Chemistry, 1997, vol. 62, # 26, p. 9099 - 9106
[2] Tetrahedron Letters, 1997, vol. 38, # 26, p. 4693 - 4696
[3] Advanced Synthesis and Catalysis, 2005, vol. 347, # 1, p. 121 - 128
[4] Advanced Synthesis and Catalysis, 2005, vol. 347, # 14, p. 1804 - 1810
[5] Advanced Synthesis and Catalysis, 2005, vol. 347, # 14, p. 1804 - 1810
[6] Advanced Synthesis and Catalysis, 2005, vol. 347, # 14, p. 1804 - 1810
[7] Biocatalysis and Biotransformation, 2015, vol. 33, # 5-6, p. 250 - 259
5
[ 51762-04-0 ]
[ 957-68-6 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 2, p. 343 - 348
6
[ 27920-90-7 ]
[ 957-68-6 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2003, vol. 345, # 6-7, p. 783 - 789
[2] Advanced Synthesis and Catalysis, 2008, vol. 350, # 2, p. 343 - 348
[3] Journal of Molecular Catalysis B: Enzymatic, 2012, vol. 76, p. 52 - 58
7
[ 64-19-7 ]
[ 107-10-8 ]
[ 957-68-6 ]
Reference:
[1] Journal of the American Chemical Society, 1984, vol. 106, # 13, p. 3820 - 3825
8
[ 27266-61-1 ]
[ 957-68-6 ]
Reference:
[1] Chemical and Pharmaceutical Bulletin, 1982, vol. 30, # 12, p. 4545 - 4547
9
[ 28242-83-3 ]
[ 957-68-6 ]
Reference:
[1] Advanced Synthesis and Catalysis, 2008, vol. 350, # 2, p. 343 - 348
10
[ 3595-18-4 ]
[ 957-68-6 ]
Reference:
[1] Journal of Molecular Catalysis B: Enzymatic, 2012, vol. 76, p. 52 - 58
11
[ 13183-79-4 ]
[ 957-68-6 ]
[ 24209-38-9 ]
Yield
Reaction Conditions
Operation in experiment
98%
Stage #1: at 10 - 12℃; for 0.166667 h; Stage #2: at 25℃; for 0.75 h; Stage #3: With chloroacetyl chloride In N,N-dimethyl-formamide at 0℃; for 0.75 h;
Into a 1000ml four-necked flask was added 132ml (141.1g, 1.57mol) dimethyl carbonate, 162g boron trifluoride-dimethyl carbonate complex, was added at 10-12 deg. C 21.5g (0.185mol) 1-methyl-5-mercaptotetrazole, after stirring for 10min was added 50g (0.184mol) 7-aminocephalosporanic acid (7-ACA), reacted at 25 deg. C, after 45min, cooled to 0 deg. C, was added dropwise 32g (0.283mol) of chloroacetyl chloride in 37ml N'N- dimethylformamide solution, the reaction was kept for 45min, the reaction mixture was added with 300ml of water and 300ml of dimethyl carbonate then stirred, separated and the aqueous layer was extracted with 400ml of dimethyl carbonate, dimethyl carbonate layers combined, added 5g active carbon for 30min, a solution of triethylamine in dimethyl carbonate was added dropwise, adjusted to pH 6.8 at 0 -5 deg. C crystallization for 2h, filtration, the filter cake was dried in vacuo at 45 deg. C, to obtain 67g (0.180mol) 7-aminocephalosporanic triazine (7-ACT), a yield of 98percent.
91.3%
With boron trifluoride diethyl etherate In acetonitrile at 50℃; for 2.5 h;
5-Mercapto-1-methyl-1H-tetrazole (6.32 g, 54.48 mmol) and7-ACA (4, 14.8 g, 54.41 mmol) were successively added toa stirred solution of BF3·Et2O (23.6 g) in anhydrous acetonitrile(75 mL). The resulting solution was allowed to reactat 50 °C for 2.5 h. After cooling in an ice-bath, the reactionsolution was diluted with H2O (75 mL) and adjusted to pH4.0 by the addition of 28 percent NH4OH. Crystals that precipitatedwere collected by filtration, and washed with waterand then acetone, to give 5 (16.3 g, 91.3 percent) as earth-yellowsolid. m.p.: 207–209 °C [lit. [37, 38]: 224–226 °C (dec.)].IR (KBr): 3423, 3170, 1803, 1735, 1618, 1542, 1411, 1342, 1084 cm−1. 1H NMR (400 MHz, DMSO-d6): δ = 3.56 (d,2J = −18 Hz, 1H, H-4), 3.73 (d, 2J = −18 Hz, 1H, H-4),3.93 (s, 3H, CH3), 4.20 (d, 2J = −13.6 Hz, 1H, CH2), 4.36(d, 2J = −13.6 Hz, 1H, CH2), 4.78 (d, 3J = 5.2 Hz, 1H, H-6),4.96 (d, 3J = 5.2 Hz, 1H, H-7).
91.3%
With boron trifluoride diethyl etherate In acetonitrile at 50℃; for 2.5 h;
1) 7-TMCA (II): A mixture of 7-ACA (14.8g, 54.41mmol), mercapto tetrazole (6.32g, 54.48mmol) and BF3· Et2O (23.6g) in anhydrous acetonitrile (75mL) The reaction solution was stirred for 50 2.5h.The reaction solution was cooled to 0 deg.] C, was added water (75mL), and treated with aqueous ammonia solution was adjusted pH = 4, filtered, and the filter cake was washed successively with water and acetone to give a yellow solid product II (16.3g, 91.3percent).
Reference:
[1] Patent: CN105330677, 2016, A, . Location in patent: Paragraph 0024
[2] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 12, p. 5534 - 5538
[3] Journal of the Iranian Chemical Society, 2016, vol. 13, # 6, p. 1019 - 1025
[4] Patent: CN105585580, 2016, A, . Location in patent: Paragraph 0007; 0031; 0032; 0033
[5] Journal of Heterocyclic Chemistry, 1989, vol. 26, # 2, p. 461 - 464
[6] Chemical and Pharmaceutical Bulletin, 1985, vol. 33, # 12, p. 5534 - 5538
[7] Pharmazie, 1987, vol. 42, # 3, p. 160 - 161
12
[ 18686-81-2 ]
[ 957-68-6 ]
[ 24209-38-9 ]
Yield
Reaction Conditions
Operation in experiment
324 g
With acetonitrile boron trifluoride complex In acetonitrile at 30℃; for 2 h;
(1) 1.5 L of acetonitrile, 300 g of 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooct-2-ene-2-carboxylic acid, 1.5 kg of 5-Mercapto-1- methyltetrazole, 1.4 L of Borontrifluoride / acetonitrile complex were mixed, then heated to 40 ° C, and rapidly stirred for 1 h. after completion of reaction, it was cooled to 2 ° C. The reaction solution was mixed with 2.25 L of purified water pre-cooled to 5 ° C and slowly stirred until the crystal was precipitated, then stir again for 30 min, add 10percent ammonia to adjust the pH to 3.4, control the temperature to 0 ~ 5 ° C, and raise the crystal for 3h. Filtration carried out, then washed twice with 1.5L of acetone, and vacuum drying to obtain white crystalline powder (6R, 7R) -7-amino-3 [(Z) -2- (4- methylthiazole) -5- yl] Vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 324g
Reference:
[1] Patent: CN106699775, 2017, A, . Location in patent: Paragraph 0029; 0030
13
[ 1918-77-0 ]
[ 957-68-6 ]
[ 153-61-7 ]
Yield
Reaction Conditions
Operation in experiment
85%
With 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride; triethylamine In dichloromethane at 30℃; for 2 h; Green chemistry
In a 2000 ml three-necked flask, 71 g of 2-thiopheneacetic acid was added.Organic solvent dichloromethane 550ml,Then add 90 ml of triethylamine and EDC (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride) 190 g.Then control the temperature to slowly add 7-ACA 110g under the condition of 30°C,And control the condensation reaction at a temperature of 30°C for 2 hours.After the condensation reaction was completed, a 10percent wt hydrochloric acid solution was added dropwise to the reaction solution to adjust the ph value to 1.5-2.0. Then,Standing, delaminating, collecting organic phases, The collected organic phase was quickly added to 1000 ml of aqueous sodium bicarbonate and the pH was adjusted to 6.5-7.0.Standing, stratified, Collect the water phase,Then control the temperature at 20-25 degrees Celsius slowly adding 10wtpercent hydrochloric acid to adjust the system ph value to 1.5,Then stir and crystallize for 1 hour, cool down to 10°C, and filter to obtain wet product.Drying at 40°C gives a white solid productCephalothin 170g, yield 85percent.
Reference:
[1] Patent: CN107793431, 2018, A, . Location in patent: Paragraph 0012; 0013; 0014; 0015; 0016; 0017; 0018; 0019
To a 2000 mL three-necked flask was added 71 g (0.5 mol) of 2-thiopheneacetic acid,Organic solvent ethylene glycol dimethyl ether 600mL,Then add 80 mL of morpholine andTrifluoroacetic acid succinimidyl ester212 g (1.0 mol), and then the temperature was programmed at a temperature of 10 ° C to 15 ° C.4.5 hours, the reaction was completed, and the reaction solution containing the active ester was obtained by filtration,The reaction solution containing the active ester was slowly added dropwise to a prefabricated solution containing 136 g (0.5 mol) of 7-ACA in 1000 mL of ethylene glycol dimethyl ether,The temperature was irradiated at 15 ° C to 25 ° C for 1 hour,After the condensation reaction was completed, the reaction solution was added dropwise with 10percent by weight hydrochloric acid solution, the pH was adjusted to 1.5 to 2.0, and then allowed to stand, the layers were collected, the organic phase was collected,The collected organic phase was rapidly added to 1000 mL of aqueous sodium bicarbonate solution, the pH was adjusted to 6.5 to 7.0,The temperature was then controlled at 20 ° C to 25 ° C, 10percent by weight hydrochloric acid was slowly added, the pH of the system was adjusted to 1.5, stirred, the crystals were raised for 1 hour,The filtrate was filtered to give a wet product and dried at 40 & lt; 0 & gt; C154 g of product was obtained as a white solid, cefuroxime, in a yield of 96.9percent.
With tetrabutyl-ammonium chloride; sodium hydroxide In methanol; water at -5 - 5℃;
Weigh 7-ACA 27.2g (0.1mol),Add 50mL of methanol and 50mL of water,Add 3.0g tetra-n-butane at -5-5°CAmmonium chloride stirring to dissolve,Maintain the addition of 2mol/L sodium hydroxide solution 105mL at this temperature.After dripping, maintain the temperature and continue stirring for 0.5-1 hour.Then add 30percent hydrochloric acid to adjust the pH to neutral,Precipitation of solids, suction filtration, anhydrous ethanol washing,20.7g of dried white solidYield 90.1percent,HPLC purity analysis 97.35percent (area normalization method),Lactone impurity 0.33percent.
86%
With water; sodium hydroxide In methanol at -20 - -10℃;
In the first step: 20 g of 7-ACA was added to a solution consisting of 140 mL of methanol and 140 mL of water, cooled to -10 to -20 ° C, 15.6 mL of a 10 mol / L NaOH solution was added dropwise, stirred for 10 min, The reaction solution was slowly neutralized with 1 mol / L HCl solution to pH to pH 3. After filtration, the filter cake was washed successively with methanol, acetone and diethyl ether and dried in vacuo to give 14.5 g White 7-AHCA, the yield was 86percent;
Reference:
[1] Patent: CN105131017, 2017, B, . Location in patent: Paragraph 0041-0042
[2] Synthetic Communications, 2003, vol. 33, # 14, p. 2475 - 2482
[3] Patent: CN106083894, 2016, A, . Location in patent: Paragraph 0045; 0054; 0055; 0056; 0057
[4] Synthesis, 2012, vol. 2012, # 2, p. 207 - 214
[5] Farmaco, 2003, vol. 58, # 6, p. 409 - 418
[6] Bioorganic and Medicinal Chemistry Letters, 2006, vol. 16, # 21, p. 5534 - 5537
[7] Journal of Medicinal Chemistry, 1984, vol. 27, # 5, p. 694 - 700
[8] Journal of Medicinal Chemistry, 1974, vol. 17, p. 1312 - 1315
[9] Canadian Journal of Chemistry, 1993, vol. 71, # 6, p. 896 - 906
[10] Bioorganic and Medicinal Chemistry Letters, 2000, vol. 10, # 9, p. 853 - 857
[11] Farmaco, 2001, vol. 56, # 8, p. 629 - 631
[12] Organic Process Research and Development, 2009, vol. 13, # 4, p. 815 - 819
[13] Patent: CN105254650, 2016, A, . Location in patent: Paragraph 0043
24
[ 957-68-6 ]
[ 56796-39-5 ]
Reference:
[1] Patent: CN105330677, 2016, A,
25
[ 957-68-6 ]
[ 56610-72-1 ]
Reference:
[1] Journal of the Iranian Chemical Society, 2016, vol. 13, # 6, p. 1019 - 1025
[2] Patent: CN105585580, 2016, A,
26
[ 110-86-1 ]
[ 354808-44-9 ]
[ 957-68-6 ]
[ 72558-82-8 ]
Yield
Reaction Conditions
Operation in experiment
98.9%
at -16℃; for 2 h; Sonication; Industrial scale
One-pot method of this invention a method of preparation Ceftazidime, comprising the steps of: weighing 272kg7-amino cephalosporanic acid (7-ACA, compound I, MW272,1000mol), 360.8 kg cephalosporin he [...] hydrochloride (compound II, MW328,1100mol) and 1027 kg pyridine (MW79,13000mol), placed in an ultrasonic reactor, -16°C, ultrasonic oscillation 800W 2 hours, adjusted to pH 4.2, is added to reaction solution 190.4 kg acetone, separating white solid, 5 °C cold water washing, 50 °C vacuum drying 5 hours to obtain the 629 kg (MW636) Ceftazidime, yield 98.9percent, purity 99.9percent or more, the single hetero less than 0.01percent, acetone residual quantity is less than 0.01percent.
Reference:
[1] Patent: CN105585582, 2016, A, . Location in patent: Paragraph 0031; 0032
Reference:
[1] Patent: CN105646535, 2016, A, . Location in patent: Paragraph 0025; 0026; 0027; 0028; 0029; 0030; 0031-0033
31
[ 533-37-9 ]
[ 80756-85-0 ]
[ 957-68-6 ]
[ 98753-19-6 ]
Yield
Reaction Conditions
Operation in experiment
99%
for 0.0666667 h; Microwave irradiation
The method for synthesizing cefpirome sulfuric acid by microwave method according to the present invention,Comprising the steps of:(1) 7-aminocephalosporanic acid (2.72 g, 7-ACA, Compound I, MW272, 0.01 mol) and AE-activity(AEMA, Compound VII, MW 350, 0.011 mol) was mixed and homogeneously ground.(Compound IV, MW 119, 0.011 mol) and concentrated sulfuric acid (10.88 g, 98percent by weight) were added to the solution, followed by the addition of 2,30 g of 2,3-cyclopentenopyridine.(2) 300W microwave reaction for 1 minute,450W microwave reaction for 1 minute,750W microwave reaction for 2 minutes;(3) After completion of the reaction,The reaction residue was added to 29.92 g of deionized water,Mixing and filtering,Take filtrate,The solvent was removed,A white solid,50 & lt; 0 & gt; C for 4 hours under vacuum,That is to get the cefpirome sulfuric acid 5.09g (MW514),Yield 99.0percentPurity 99.9percent or more.
Reference:
[1] Patent: CN105646542, 2016, A, . Location in patent: Paragraph 0027; 0040; 0041; 0042; 0043; 0044; 0045
Stage #1: 7-Aminocephalosporanic acid With chloro-trimethyl-silane; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane at 20℃; for 1h;
Stage #2: chloroacetyl chloride With copper oxide (I) at 0 - 20℃; for 1h;
1; 2; 3; 4 Example 3 Preparation of chloroacetyl 7-ACA
Add 60mL of dichloromethane to a 250mL reaction flask, and add 7-ACA10.88g while stirring.Add 9.68g of hexamethyldisilazane,Trimethylchlorosilane 3.48g,Stir for 1h at room temperature,The reaction was monitored by HPLC for completion,Cool down to 0-10C,Add 1.61g of cuprous oxide,Slowly add 4.93 g of chloroacetyl chloride,After the addition is completed, the temperature is raised to room temperature.After 1h, the reaction was detected by HPLC.filter,The filtrate is weighed,Concentrate under reduced pressure at 35C until the weight of the filtrate is halved.Add 120mL of purified water,Stir at room temperature,Precipitation of crystals,Cultivate for 30min,Suction filtration,Washed with purified water,Vacuum drying at 45 C for 2h,13.08g of chloroacetyl 7-ACA white powder,Color level
88.4%
With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; propan-2-one for 3h;
85%
With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; propan-2-one at 4 - 17℃; for 3.5h;
4 Example 4 Operation example of TM1kTM1y synthesis
General procedure: Add 7-AXCA (5mmol),5mL of acetone and 1mL of water,Stir at room temperature,Add sodium bicarbonate (1.26g, 1.5mmol),In an ice salt bath, add acid chloride (1.0 mmol) dropwise,Stir. TLC monitors the progress of the reaction.After the reaction is complete,Add ice-cold 2NHCl to adjust pH=7,Spin off the solvent acetone,Freeze to precipitate solids,Add ice-cold 2NHCl to adjust pH=3,A large amount of solid precipitated out.Suction filtration, drying,Obtain solid TM1kTM1y.The experimental results are shown in Table 7.
In ethyl acetate
With potassium carbonate In propan-2-one at 0 - 30℃; for 5h;
4-6
7-Aminocephalosporanic acid was added to the solvent and stirred, anhydrous potassium carbonate was added, chloroacetyl chloride was slowly added dropwise in an ice-water bath, and then stirred at room temperature until the reaction was completed to obtain the target compound III. The molar ratio of 7-aminocephalosporanic acid, chloroacetyl chloride and anhydrous potassium carbonate is 1:1.2:2, the solvent is dioxane, the reaction temperature is 0-30, and the reaction time is 5h.
(6<i>R</i>)-3-acetoxymethyl-7<i>t</i>-[2-(dimethyl-thiocarbamoylsulfanyl)-acetylamino]-8-oxo-(6<i>r</i><i>H</i>)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
(i) Et3N, isovaleryl chloride, (ii) /BRN= 622638/; Multistep reaction;
With tetrabutyl-ammonium chloride; sodium hydroxide; In methanol; water; at -5 - 5℃;
Weigh 7-ACA 27.2g (0.1mol),Add 50mL of methanol and 50mL of water,Add 3.0g tetra-n-butane at -5-5°CAmmonium chloride stirring to dissolve,Maintain the addition of 2mol/L sodium hydroxide solution 105mL at this temperature.After dripping, maintain the temperature and continue stirring for 0.5-1 hour.Then add 30percent hydrochloric acid to adjust the pH to neutral,Precipitation of solids, suction filtration, anhydrous ethanol washing,20.7g of dried white solidYield 90.1percent,HPLC purity analysis 97.35percent (area normalization method),Lactone impurity 0.33percent.
86%
With water; sodium hydroxide; In methanol; at -20 - -10℃;
In the first step: 20 g of 7-ACA was added to a solution consisting of 140 mL of methanol and 140 mL of water, cooled to -10 to -20 ° C, 15.6 mL of a 10 mol / L NaOH solution was added dropwise, stirred for 10 min, The reaction solution was slowly neutralized with 1 mol / L HCl solution to pH to pH 3. After filtration, the filter cake was washed successively with methanol, acetone and diethyl ether and dried in vacuo to give 14.5 g White 7-AHCA, the yield was 86percent;
With ammonium hydroxide; In water; at 25℃; for 1h;pH 7.5;
A solution of 60 g (0.221 mol) of 7-ACA was added to a reaction vessel, dispersed in 300 ml of water, 10percent aqueous ammonia was added dropwise, the pH of the solution was adjusted to 7.5, the temperature was controlled at 25 ° C to dissolve completely, and 45 g of solidified enzyme 60 minutes, the reaction completed, filter out the curing enzyme, and then to the solution by adding 50ml of ethyl acetate; start dropping 2-thiophene acetyl chloride 35g, 2h drop finished, and then continue to heat 1h; insulation completed, drop 10percent The solution was cooled to 5 ° C to precipitate crystals, filtered and dried to obtain 95.6 g of desacetyl cefotaxel benzoate salt in a yield of 91.1percent.
With boron trifluoride dimethyl carbonate complex; acetic acid; at 5 - 10℃;
The boron trifluoride-dimethyl carbonate complex (2.5 mol) was dissolved in 150 ml of dimethyl carbonate, and then 132.26 g (1 mol) of compound II was added. The solution was stirred and dissolved at room temperature, and the temperature was controlled at 5-10 C Add glacial acetic acid (1mol), and then slowly add 7-ACA 299.51g (1.1mol), control at 5-10 for 1-1.5h, transfer to water, adjust the pH to 3.8 with ammonia water, precipitate crystals, and grow. The crystal was crystallized for 1 h, filtered, washed with purified water, and dried under vacuum to obtain compound III327.21g, with a molar yield of 95%, a purity of 99.4%, and a maximum single impurity of 0.08%.
92.1%
With boron trifluoride dimethyl carbonate complex; carbonic acid dimethyl ester; at 20 - 30℃; for 1h;
(1) Add 500 mL of dimethyl carbonate and 9.86 g of 2-hydroxysuccinic acid to a 500 mL three-necked flask, add 4.85 g of MMTD with stirring, and add 10.00 g of 7-ACA.Slowly adding 40.62g of boron trifluoride-dimethyl carbonate complex,The temperature was controlled at 20 to 30 C, and after 1 h, the HPLC monitoring reaction was completed.Add 1.28 g of sodium dithionite, stir for 10 min, transfer to water and add 80 mL of n-butanol, slowly add triethylamine to adjust the pH to 4.5, control the dropping time for 30-60 min, and cool down to 0-10 C for 1 h. The mixture was suction filtered and dried under vacuum to give a crystals of 7-tDA, 11.65 g, yield 92.1%, purity by HPLC, 99.2%, and the maximum amount of 0.10%.
Into a 1000ml four-necked flask was added 132ml (141.1g, 1.57mol) dimethyl carbonate, 162g boron trifluoride-dimethyl carbonate complex, was added at 10-12 deg. C 21.5g (0.185mol) 1-methyl-5-mercaptotetrazole, after stirring for 10min was added 50g (0.184mol) 7-aminocephalosporanic acid (7-ACA), reacted at 25 deg. C, after 45min, cooled to 0 deg. C, was added dropwise 32g (0.283mol) of chloroacetyl chloride in 37ml N'N- dimethylformamide solution, the reaction was kept for 45min, the reaction mixture was added with 300ml of water and 300ml of dimethyl carbonate then stirred, separated and the aqueous layer was extracted with 400ml of dimethyl carbonate, dimethyl carbonate layers combined, added 5g active carbon for 30min, a solution of triethylamine in dimethyl carbonate was added dropwise, adjusted to pH 6.8 at 0 -5 deg. C crystallization for 2h, filtration, the filter cake was dried in vacuo at 45 deg. C, to obtain 67g (0.180mol) 7-aminocephalosporanic triazine (7-ACT), a yield of 98%.
91.3%
With boron trifluoride diethyl etherate; In acetonitrile; at 50℃; for 2.5h;
5-Mercapto-1-methyl-1H-tetrazole (6.32 g, 54.48 mmol) and7-ACA (4, 14.8 g, 54.41 mmol) were successively added toa stirred solution of BF3·Et2O (23.6 g) in anhydrous acetonitrile(75 mL). The resulting solution was allowed to reactat 50 C for 2.5 h. After cooling in an ice-bath, the reactionsolution was diluted with H2O (75 mL) and adjusted to pH4.0 by the addition of 28 % NH4OH. Crystals that precipitatedwere collected by filtration, and washed with waterand then acetone, to give 5 (16.3 g, 91.3 %) as earth-yellowsolid. m.p.: 207-209 C [lit. [37, 38]: 224-226 C (dec.)].IR (KBr): 3423, 3170, 1803, 1735, 1618, 1542, 1411, 1342, 1084 cm-1. 1H NMR (400 MHz, DMSO-d6): delta = 3.56 (d,2J = -18 Hz, 1H, H-4), 3.73 (d, 2J = -18 Hz, 1H, H-4),3.93 (s, 3H, CH3), 4.20 (d, 2J = -13.6 Hz, 1H, CH2), 4.36(d, 2J = -13.6 Hz, 1H, CH2), 4.78 (d, 3J = 5.2 Hz, 1H, H-6),4.96 (d, 3J = 5.2 Hz, 1H, H-7).
91.3%
With boron trifluoride diethyl etherate; In acetonitrile; at 50℃; for 2.5h;
1) 7-TMCA (II): A mixture of 7-ACA (14.8g, 54.41mmol), mercapto tetrazole (6.32g, 54.48mmol) and BF3· Et2O (23.6g) in anhydrous acetonitrile (75mL) The reaction solution was stirred for 50 2.5h.The reaction solution was cooled to 0 deg.] C, was added water (75mL), and treated with aqueous ammonia solution was adjusted pH = 4, filtered, and the filter cake was washed successively with water and acetone to give a yellow solid product II (16.3g, 91.3%).
With sulfuric acid In 1,2-dimethoxyethane at 5℃; for 72h;
50%
With sulfuric acid In 1,4-dioxane at 0 - 20℃; for 2h;
1 Synthesis of (6R,7R)-tert-butyl-3-(acetoxymethyl)-7-amino-8-oxo-5-thia-1-aza- bicyclo[4.2.0]oct-2-ene-carboxylate (7).
Isobutene (32 mL) was added to a mixture of 7-aminocephalosporanic acid (7-ACA) (7.0 g, 25.71 mmols) and cone. H2S04 (6.42 mL) in anhydrous dioxane (64 mL), placed at 0°C. The reaction mixture was stirred at room temperature for 2 hours. The mixture was then adjusted to an alkaline pH by adding a saturated solution of NaHC03, extracted with AcOEt (3 x 200 mL), washed with brine (5 x 100 mL), dried and evaporated to give a brown oil. The crude product was then purified by crushing with -hexane to give pure 7 as a yellow solid (4.154 g, 50% yield). 1H-NMR (CDCl3) δ: 1.56 (s, 9H); 2.11 (s, 3H); 2.02-2.05 (brs, 2H); 3.40-3.57 (2d, J = 18.2 Hz, 2H); 4.78-4.85 (m, 2H); 5.0 (d, J= 5.1 Hz, 1H); 5.07 (d, J= 13.2 Hz, 1H).
With triethylamine In 1,4-dioxane; water at 20℃; for 24h;
6 Synthesis of (6R,7R)-3-(acetoxymethyl)-7-(tert-butoxy-carbonylamino)-6-oxo-5-thio- 1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
1 g (3.673 mmoles) of 7-ACA (7-amino-cephalosporinic acid) was suspended, in a 100 ml flask, in 30 ml of a solution of water and dioxane in a ratio of 1: 1 by volume, at room temperature. After the addition of 1.023 ml (7.346 mmoles) of TEA, a complete solubilization was obtained. 1.042 g of di-ie/t-butyl dicarbonate (4.775 mmoles) where then added to this solution and the solution was kept under stirring at room temperature for 24 hours. (0155) The reaction trend was monitored by means of thin layer chromatography (TLC) with DMC/methanol 9.5:0.5 as solvent and when the starting reagent had been totally consumed, the dioxane was removed by means of evaporation at reduced pressure. The compound thus obtained was extracted using DCM (3x50 ml) and the organic phase was dried on NaS04. The organic solvent was then removed under vacuum obtaining a white foam with a yield of 90%. (0156) The compound thus obtained was extracted using DCM (3x50 ml) and the organic phase was dried on NaS04. The aqueous phase was dried and 0.930 g of a yellow solid were obtained as a mixture of starting material and compound (VII) which was purified by means of flash chromatography obtaining a white solid with a yield of 70%. (0157) (0158) (VIII) (0159) 1H-NMR (400 MHz, CDC13): δ 13.38 (br, 1H, COOH), 5.53 (dd, = 9.7, 4.7 Hz, 1H, H6-p-lactam), 5.21 (d, = 9.8 Hz, 1H, H7-p-lactam), 5.11 (d, = 12.6 Hz, 1H, H/ β- lactam ), 4.97 (d, = 4.8 Hz, 1H, H5-p-lactam), 4.93 (d, = 12.6 Hz, 1H, H2-p-lactam), 3.51 (d, = 17.8 Hz, 1H, H3-p-lactam), 3.26 (d, = 17.8 Hz, 1H, H4-p-lactam), 2.04 (s, 3H-CH3), 1.43 (s, 9H, 3-CH3). (0160) 13C-NMR (100 MHz, CDC13): δ 171.10 (s, 1C, CH3C=0), 166,87 (s,lC,-NC=0, Cp- lactam), 164.97 (s, 1C, -OC=0, C2p-lactam), 154.37(s, 1C, C=0 Boc), 132.34, (s, 1C, p-lactam), 116,48 (s, 1C, Qp-lactam), 80.98 (s, 1C, -C(CH3)3), 64,35 (s, 1C, Q3- lactam), 60.84 (s, 1C, C/p-lactam), 57.75 (s, 1C, C3-lactam), 28.32 (s, 3C, -C(CH3)3), 26.65 (s, 1C, C5p-lactam ), 21.08 (s, 1C, CH3C=0) (0161) 1 13 (0162) The H-NMR C-NMR spectra of the compound having formula (VII) are shown in figures 19-23.
With sodium hydrogencarbonate In 1,4-dioxane; water for 120h; Ambient temperature;
Stage #1: 7-Aminocephalosporanic acid With anhydrous sodium carbonate In lithium hydroxide monohydrate; propan-2-one at -5℃; for 0.166667h;
Stage #2: 2-phenylacetyl chloride In lithium hydroxide monohydrate; propan-2-one for 4h;
Stage #3: With hydrogenchloride In lithium hydroxide monohydrate; ethyl acetate; propan-2-one
87%
With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; propan-2-one at 0 - 20℃; for 18h;
83%
With Sodium hydrogenocarbonate In propan-2-one at 20℃; for 17h;
55%
Stage #1: 7-Aminocephalosporanic acid; 2-phenylacetyl chloride With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; propan-2-one at 20℃; for 16h;
Stage #2: With hydrogenchloride In dichloromethane; lithium hydroxide monohydrate; propan-2-one
55%
With Sodium hydrogenocarbonate In dichloromethane
45%
Stage #1: 7-Aminocephalosporanic acid With sodium carbonate monohydrate In lithium hydroxide monohydrate at 0℃; for 0.0833333h;
Stage #2: 2-phenylacetyl chloride In lithium hydroxide monohydrate; propan-2-one at 0 - 20℃; for 0.5h;
Example 6
Example 5.General Procedure for the Acylation of 7-Aminocephalosporanic Acid.7-aminocephalosporanic acid (7-ACA) [00177] According to the method described by Cocker et al. (Cocker, J. D.; Cowley, B. R.; Cox, J. S. G.; Eardley, S.; Gregory, G. I; Lazenby, J. K.; Long, A. G; Sly, J. C, P.;Somerfield, G. A. J. Chem. Soc, 1965, 5015-5031), 7-ACA (272 mg, 1.0 mmol) was added to a stirring solution of Na2C03 H20 (200 mg, 1.6 mmol) in H20 (4 mL) at 0 °C, This solution was stirred for 5 min at 0 °C before the dropwise addition of the acid chloride (1.1 mmol), followed by the addition of acetone (1 mL). The mixture was stirred for 30 min at 0 °C and then allowed to warm to room temperature overnight. The mixture was diluted with H20 (40 mL) and adjusted to pH 2 with the addition of 2 N HQ. The resulting precipitate was filtered and dried under vacuum.Example 6.(6R,7R)-3-(acetoxymethyl)-8-oxo-7-(2-phenylacetamido)-5-thia-l azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.[00178] The title compound was isolated as a yellow solid (175 mg, 45%) following the general procedure for acylation described above. 1H NMR (300 MHz, DMSO-i/6): δ 9.10 (d, J= 8.3 Hz, 1H), 7.32-7.18 (m, 5H), 5.67 (dd, J= 8.3 Hz, J= 4.8 Hz, 1H), 5.07 (d, J= 4.8 Hz, 1H), 4.99 (d, J= 12.8 Hz, 1H), 4.67 (d, J= 12.8 Hz, 1H), 3.61 (d, J= 18.1 Hz, 1H), 3.56 (d, J= 13.8 Hz, 1H), 3.48 (d, J= 13.8 Hz, 1H), 3.47 (d, J= 18.1 Hz, 1H), 2.02 (s, 3H). LRMS (+ESI) /// : 408 [M + H20]+, 391 [M + H]+.
31%
With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; propan-2-one at 20℃; for 0.5h; Inert atmosphere;
31%
With Sodium hydrogenocarbonate In lithium hydroxide monohydrate; propan-2-one at 20℃; for 0.5h;
Method A
General procedure: 7-ACA (1 equiv) was dissolved in sat. NaHCO3 (aq) and acetone added, followed by acid chloride (1.2 or 2 equiv). The reaction was stirred at room temperature for 30 mm then washed with EtOAc. The aqueous layer was acidified to pH 2 with 1 M HCI and extracted with DCM (x3). The organic extracts were combined, dried over Na2SO4, evaporated and the resulting solid triturated with ice- cold Et20 (unless otherwise stated) to afford the product.
(6R,7R)-7-(α-methylcinnamoyl)amino-3-acetoxymethyl-3-cephem-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
50.1%
Stage #1: 2-methyl-3-phenylacrylic acid; 7-Aminocephalosporanic acid With N,O-bis-(trimethylsilyl)-acetamide; N,N-dimethyl-formamide; trichlorophosphate In tetrahydrofuran; ethyl acetate at -20℃; for 1h;
Stage #2: With water In tetrahydrofuran; ethyl acetate
(6R,7R)-7-(2'-methoxycinnamoyl)amino-3-acetoxymethyl-3-cephem-4-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
75.5%
Stage #1: 2-methoxycinnamic acid; 7-Aminocephalosporanic acid With N,O-bis-(trimethylsilyl)-acetamide; N,N-dimethyl-formamide; trichlorophosphate In tetrahydrofuran; ethyl acetate at -20℃; for 1h;
Stage #2: With water In tetrahydrofuran; ethyl acetate
Stage #1: 7-Aminocephalosporanic acid With N,O-bis-(trimethylsilyl)-acetamide In dichloromethane at 20℃; for 1h;
Stage #2: diethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate In dichloromethane at 20℃; for 8h;
Stage #3: With sodium hydroxide In dichloromethane; water at 15 - 20℃;
5 EXAMPLE 5
EXAMPLE 5 10 g of 7-aminocephalosporanic acid are suspended in 70 ml of dichloromethane. 7.9 g of N,O-bis-(trimethylsilyl)acetamide are added and the mixture is agitated for 1 h at ambient temperature. 8.1 g of diethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate are added and the mixture left to react at ambient temperature for 8 hours. On termination of the reaction the synthesis mixture is dripped into 80 ml of water at +15/+20° C., adjusting the PH to 7.5-7.8 with 15% NaOH during the dripping. The aqueous phase is separated, diluted with 16 ml of isopropyl alcohol and then with water to a total of 195 ml. 5 ml of ethyl acetate are added to the solution obtained, it is cooled to 0° C. and 15% HCl added until PH 3.5 is achieved, where the first crystals appear.The mixture is agitated for 30 min and the PH then lowered to 2.7.It is again agitated for 30 min and filtered, washing with acetone. It is dried at +40° C. under reduced pressure. 8.5 g of cefotaxime acid are obtained. Molar yield: 94.4%. cefotaxime is a compound of formula (I) in which R1 is acetoxy, R2 is methoxyl and R3 is hydrogen.
93.5%
Stage #1: 7-Aminocephalosporanic acid With N,O-bis-(trimethylsilyl)-acetamide In DMF (N,N-dimethyl-formamide) at 20 - 25℃;
Stage #2: diethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate In DMF (N,N-dimethyl-formamide) at 20℃; for 18h;
6 EXAMPLE 6
EXAMPLE 6 5.0 g of 7-aminocephalosporanic acid are suspended in 35 ml of anhydrous DMF. 7.3 g of N,O-bis-(trimethylsilyl)acetamide are added while maintaining the temperature at +20°/+25° C. The 7-aminocephalosporanic acid dissolves rapidly and totally. 7.5 g of diethylthiophosphoryl-(Z)-(2-aminothiazol-4-yl)methoxyimino acetate are added and the mixture left to react at ambient temperature for 18 hours.On termination of the reaction 65 ml of water and 65 ml of methylene chloride are added. The mixture is adjusted to PH 7 with NaHCO3 and the phases are separated.The aqueous phase is washed repeatedly with dichloromethane. 6 ml of isopropyl alcohol are added to the aqueous phase and then diluted to a total of 195 ml with water. 5 ml of ethyl acetate are added to the solution obtained, it is cooled to 0° C. and 15% HCl added until PH 3.5 is achieved, where the first crystals appear.The mixture is agitated for 30 min and the PH then lowered to 2.7. It is again agitated for 30 min and filtered, washing with acetone. It is dried at +40° C. under reduced pressure. 7.7 g of cefotaxime acid are obtained. Molar yield: 93.5%.
7β-amino-3-[(imidazo[1,2-b]pyridazinium-1-yl)methyl]-3-cephem-4-carboxylate hydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
7-aminocephalosporanic acid (100 g), dichloromethane (700 ml), hexamethyldisilazane (180 g) and imidazole (1 g) were combined together at 2O0C to250C. The reaction mixture was heated to reflux temperature for 5 hours to obtain a clear solution and cooled to -1O0C to -80C.; Step b: Iodine (84 g) and dichloromethane (400 ml) were combined together at 2O0C to 250C, stirred for 5 minutes to 10 minutes and cooled to 1O0C to 150C. Hexamethyldisilane (80 g) was added to the mixture in 30 minutes to 40 minutes at 1O0C to 250C. The reaction mixture was heated to reflux temperature for 4 hours and cooled to 50C to 1O0C.Step c: The solution of step b) was added to the solution of step a) at -1O0C to O0C over a 30 minute to 40 minute duration and stirred for 2 hours at 50C to 1O0C. Imidazo[l,2,b]pyridazine (153 g) was dissolved in dichloromethane (200 ml) at 2O0C to 250C and added to the reaction mixture at 50C to 1O0C over a 15 minute to 20 minute duration. The reaction mixture was heated to 350C to 380C for 5 hours and cooled to -50C to O0C. A cooled (50C to 1O0C) mixture of methanol (250 ml) and concentrated hydrochloric acid (80 ml) was added to the reaction mixture at -50C to O0C in 30 minutes duration to obtain a pH of 2 to 2.5. The reaction mixture was stirred at O0C to 50C for 60 minutes. The slurry was filtered, washed with methanol (300 ml) and dried by suction. The solid obtained was suspended in de-mineralized water (500 ml) at 1O0C to 150C. The pH was adjusted to about 8.0 with 10% w/v sodium hydroxide solution (200 to 250 ml) at 1O0C to 150C to obtain a clear solution. Dichloromethane (500 ml) was added to the reaction mixture and stirred for 10 minutes to 15 minutes. The aqueous layer was separated and cooled to 1O0C. The pH of the aqueous layer was adjusted to about 0.8 with 6 N hydrochloric acid solution (120 to 140 ml) at 1O0C to 150C. The pH was readjusted to about 2.2 using 10% w/v sodium hydroxide solution (100 to 120 ml) and stirred for 60 minutes at 1O0C at a pH of about 2.2. The solid was filtered, washed with acetone (200 ml) and dried by suction. The wet solid obtained (150-160 g) was suspended in de- mineralized water (500 ml) at 1O0C to 150C. The pH was adjusted to about 8.0 with 10% w/v sodium hydroxide solution (100 to 120 ml) to obtain a clear solution. The pH of solution was readjusted to about 6.7 with 2 to 3 ml of 6 N hydrochloric acid solution and activated carbon (10 g) was added at 1O0C. The reaction mixture was stirred for 20 minutes at 1O0C to 150C, filtered and washed with de-mineralized water (300 ml). The pH was readjusted to about 2.2 with 6 N hydrochloric acid solution (40 to 50 ml) at 1O0C to 150C and stirred for 60 minutes at 1O0C to 15C. The solid was filtered, washed with acetone (200 ml) and air dried at 4O0C to 450C to obtain the title compound.Yield: 100 g
7-Aminocephalosporanic acid was obtained from Fisher BioReagents (MW 272.3). <strong>[60-00-4]EDTA</strong> (free acid) was from Aldrich (MW 292.24) and EDC from TCI America. All other reagents and solvents were of the highest available purity and used as purchased. [00120] In a small glass crimp cap vial with rubber septum, 12 mg <strong>[60-00-4]EDTA</strong> (0.041 mmole) was mixed with 300muEpsilon Dry DMSO. The mixture was heated on a hot-plate to complete dissolution of <strong>[60-00-4]EDTA</strong>. After cooling down the solution to room temperature, 8 mg of EDC (0.042 mmole) was added and mixed at room temperature for 30min. Then, 5 mg of NHS (0.043 mmole) was added to the mixture and mixed for another 30min. 13.6 mg amoxicillin (0.05 mmole) was added to activated <strong>[60-00-4]EDTA</strong>, and the reaction was mixed overnight at room temperature (pH 7-8). [00121] <strong>[60-00-4]EDTA</strong>CA was purified from the reaction mixture using two different chromatographic techniques. In the first step, anionic-HPLC purification was carried out on a PolyWAX LP column (4.6x250 mm, from PolyLC Inc.). Before anionic-HPLC, 1 mL of 20mM Tris buffer pH7.3 was added to the reaction mixture and pH was adjusted to -7.3 by addition of 1M NaOH. The sample was applied to the anionic column (2 runs), previously equilibrated with 20mM Tris pH7.3. The column was washed (0.7mL/min) with a linear gradient (0 to 0.5 M NaCl in 60 min) using buffer Tris 20mM +1M NaCl pH7.3. Fractions collected from anionic-HPLC were analyzed by ESI. The fractions containing product (20-26 min) were pooled and applied to a reversed phase column (CI 8 Semi-prep, 10 x 250mm, Vydac) without any TFA in the solvents (Water and acetonitrile). The fraction containing the product from RP column was concentrated in Speed- Vac to remove the acetonitrile. <strong>[60-00-4]EDTA</strong>-7-aminocephalosporanic acid (<strong>[60-00-4]EDTA</strong>CA) was quantitated in the final solution using Ni titration method. The copper chelate of the product (Cu-<strong>[60-00-4]EDTA</strong>MP) was prepared and used for further studies. [00122] The fraction at 33-37min in anionic-HPLC showed the MW of 800 in ESI which is the <strong>[60-00-4]EDTA</strong> coupled to two molecules of 7-aminocephalosporanic acid (EDT(ACA)2) (292+2(272) -2(18) = 800). It was purified using RP-HPLC and the product EDT(ACA)2 was quantitated. The Cu-EDT(ACA)2 was prepared and used for further studies
Stage #1: 7-Aminocephalosporanic acid With potassium carbonate In water; acetone at -5℃; for 0.166667h;
Stage #2: [4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]acetyl chloride In water; acetone at -5 - 20℃; for 1h;
3.1.12.1 (6R,7R)-3-[(Acetyloxy)methyl]-7-([4-(2-fluoro-4-nitrophenyl)piperazin-1-yl]acetyl}amino)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (13
7-ACA (10mmol) was added to the solution of K2CO3 (11mmol) in 4mL of water and 3mL of acetone cooled to-5°C and the resulting solution was stirred at this temperature for 10min. Then, the solution of the corresponding compound 12 (11mmol) in acetone was added drop wise in a period of 2.5-3h. After the addition was completed, the reaction mixture was stirred at room temperature for 1h. Water was added into it, and the mixture was stirred for another 1h. The reaction mixture was acidified to pH 3 with 10% HCl, the resulting precipitate was filtered off and recrystallized from acetone. M.p.: 178-180°C, yield: 86%. FT-IR (νmax, cm-1): 3145 (NH+OH), 1794 (C=O), 1735 (C=O), 1661 (2C=O), 1511 and 1334 (NO2), 1228 (C-O). Elemental analysis for C22H24FN5O8S calculated (%) C: 49.16; H: 4.50; N: 13.03. Found (%) C: 49.18; H: 4.40; N: 12.63. 1H NMR (DMSO-d6) δ ppm: 2.01 (s, 3H, CH3), 3.30 (brs, 4H, 2CH2), 3.54 (brs, 6H, 3CH2+H2O), 4.43 (s, 2H, CH2), 4.67 (s, 1H, CH), 4.82 (s, 1H, CH), 4.99 (s, 2H, CH2), 7.17 (t, 1H, ar-H, J=9.0Hz), 8.0-8.05 (m, 2H, ar-H). 13C NMR (DMSO-d6) δ ppm: 21.03 (CH3), 25.18 (CH2), 41.30 (CH2), 41.88 (CH2), 44.87 (CH2), 48.96 (CH2), 49.00 (CH2), 58.21 (CH), 62.76 (CH2), 62.81 (CH), 112.13 and 112.39 (d, CH, J=26Hz), 118.12 and 118.16 (d, CH, J=4.0Hz), 121.23 (CH), 123.04 (C), 126.43 (C), 139.58 and 139.66 (d, C, J=8.0Hz), 144.92 and 144.97 (d, C, J=5.0Hz), 150.77 and 153.22 (d, C, J=245.0Hz), 163.05 (C=O), 164.78 (C=O), 168.68 (C=O), 170.20 (C=O). LC-MS: 560.10 ([M+Na]+, 22), 491.17 ([(M-1)-CO2H]+, 22), 313.07 (100).
With sodium hydrogencarbonate In water; acetone at 20℃; for 1.5h; Cooling with ice;
1.1 Step (1): Compound 1a → Compound 1b
Compound 1a (54.5 g, 200 mmol) and sodium hydrogen carbonate (42.0 g, 500 mmol) were dissolved in a mixture of water (1000 ml)/acetone (400 ml), and then allyl chloroformate (25.6 ml, 240 mmol) was added under ice-cooling. The mixture was stirred for 30 minutes under ice-cooling, and for 1 hour at room temperature. The reaction solution was concentrated in vacuo, and then diluted with ethyl acetate, and extracted with water. The aqueous layer was made acidic, extracted with ethyl acetate, washed with brine, and dried with magnesium sulfate. Magnesium sulfate was filtered off, and the liquid was concentrated in vacuo to yield the concentrated Compound 1b (66.39 g, 93%). 1H-NMR (DMSO-d6) δ: 8.42 (1H, d, J = 8.73 Hz), 5.97-5.85 (1H, m), 5.54 (1H, dd, J = 8.73, 4.84 Hz), 5.30 (1H, dd, J = 17.23, 1.53 Hz), 5.20 (1H, dd, J = 10.37, 1.53 Hz), 5.08 (1H, d, J = 4.84 Hz), 4.98 (1H, d, J = 12.73 Hz), 4.68 (1H, d, J = 12.73 Hz), 4.53 (2H, d, J = 5.19 Hz), 3.62 (1H, d, J = 18.07 Hz), 3.48 (1H, d, J = 18.07 Hz), 2.03 (3H, s).
With water; sodium hydroxide In methanol at -10 - 0℃;
1 Example 1: Synthesis of 7-DACA and Boc-7-DACA sodium salt
Example 1: Synthesis of 7-DACA and Boc-7-DACA sodium saltThe 10.0g 7-ACA were suspended in 30mL of methanol / water solvent mixture. It was cooled to -10deg. C - 0 deg. C. Then added dropwise a solution of 30 mL 10% NaOH (added in portions). Maintaining the temperature stabilized, stirred 2h, TLC tracking reaction. When, the 7-ACA starting material point disappears, the reaction iscomplete. Then the reaction system was added to the cold acetone Solution, with vigorous stirring, gradually pale yellow solid precipitation. Filtered, drained, dried over anhydrous recrystallized from ethanol to obtain the product 7-DACA, yield 86%.
With boron trifluoride dimethyl carbonate complex; methanesulfonic acid; at 10 - 12℃; for 0.383333h;
The dried four-necked flask was added with 120 g of dimethyl carbonate, boron trifluoride dimethyl carbonate 56 g, methanesulfonic acid 8 g, quickly cool down to 10 C, adding triazine ring 15g, 7-ACA 25g, maintain 10 ~ 12 C reaction for about 23min, samples were detected by HPLC (High Performance Liquid Chromatography). The 7-ACA residue was less than 1%. To the four-necked flask by adding cold water 240g, solution clarification, adding EDTA-2Na 0.25g, Sodium dithionite 1.0g holding temperature below 13 C, dropping diluted ammonia (1: 1) to adjust pH = 2.3 to 2.6, pPrecipitation of white solid, dropwise 5 ~ 10 C crystal growing 1h, filter, the filter cake was washed twice with 120 g of water, filter, wash the filter cake with 50 g of ethanol once, filtration, vacuum drying at 45 C for 8h a solid 32.5g, molar yield 95.1%, purity 99.40%.
90%
With boron trifluoride dimethyl carbonate complex; edetate disodium; at 30℃; for 0.833333h;
In 1000ml three mouth Bottle in order to join:Dimethyl carbonate (200 ml),7-ACA (35 g, 128.5 mmol),TauTauZeta (20 · 5g, 128 · 8mmol),EDTANa2 (0.4 g, 1.2 mmol)And boron trifluoride-dimethyl carbonate solution (188 ml, 493.1 mmol)(Mass percentage content 20%),The reaction was stirred for 50 minutes at a temperature of 30 C.The temperature of the reaction was reduced to T <15 C,The reaction was terminated by addition of an aqueous solution of sodium hydrogensulfite (250 ml of water +3.5 g of NaHS03)Followed by dropwise addition of 5% aqueous ammonia seed crystal to the system turbidity, slow stirring culture 40min.Then, the pH value of the system was adjusted to 3.8-4.0 by adding 5% aqueous ammonia, and the crystal was slowly incubated for 30 min and the temperature was controlled at 6-7 C.40ml acetonitrile + 40ml washing, two wash with 90ml acetone wash, dry, vacuum dried at 50 C 2h products 42g, molar yield 90%, HPLC purity 99. 2%
85.71%
With boron trifluoride; In acetonitrile; at 10 - 30℃; for 0.5h;
In a three-necked flask, 100 mL of acetonitrile was added,7-ACA40g (147 mmol),40.4 g (254 mmol) of TTA,Stirring down to 10 C below,150 mL of boron trifluoride-acetonitrile solution [w / w = 18%] was added,The temperature was raised to 30 C and the reaction was carried out for 30 min.Add purified water 300mL in 15min,Heating to 10 ~ 20 reaction 2h,Adding the ammonia water to adjust the reaction liquid to pH 1.6-2.0,The temperature was lowered to 10 C. Filtration, filter cake with acetonitrile - water,Washed with water and dried to obtain 48 mg of 7-ACT in a yield of 85.71%.
One-pot method of this invention a method of preparation Ceftazidime, comprising the steps of: weighing 272kg7-amino cephalosporanic acid (7-ACA, compound I, MW272,1000mol), 360.8 kg cephalosporin he [...] hydrochloride (compound II, MW328,1100mol) and 1027 kg pyridine (MW79,13000mol), placed in an ultrasonic reactor, -16C, ultrasonic oscillation 800W 2 hours, adjusted to pH 4.2, is added to reaction solution 190.4 kg acetone, separating white solid, 5 C cold water washing, 50 C vacuum drying 5 hours to obtain the 629 kg (MW636) Ceftazidime, yield 98.9%, purity 99.9% or more, the single hetero less than 0.01%, acetone residual quantity is less than 0.01%.
The synthesis method comprising the steps of: a,Synthesis reaction: To the condensation reaction tank, 500 L of acetone,Water 60L,The stirring was started and the temperature was lowered to 10 C,7-ACA was added at 70 kg,AE active ester 95 kg,After stirring the reaction for 10 minutes,And then cooled to 10 C,A 12% (by mass) solution of sodium hydroxide was slowly added dropwise over 120 minutes with stirring,With stirring the solution to clear,The pH of the solution was adjusted to 9.5 by detecting the pH of the solution,Stop dropping,start the timer,The reaction was continued at 15 C for 60-90 minutes,The reaction was allowed to proceed for 60 minutes. Sampling was carried out. The 7-ACA content in the solution was determined by high performance liquid chromatography (HPLC)When the residual amount of 7-ACA is less than or equal to 0.5%, the stirring reaction is stopped,Thereby obtaining a reaction solution; b, bleaching,filter:To the reaction solution obtained in step a, 6 kg of activated carbon was added,Stirred for 15 minutes,And then filtered through the frame,After sterile filtration,The sterile filtrate obtained is passed into a sterile chamber crystallization tank,And the filter was rinsed with 90 L of an 80% (volume) acetone solution,Into a sterile crystallization tank; c, crystallization: c1, to the crystallization tank and then add acetone 360L,Sodium metabisulfite 1.2 kg,Then adding cefotaxime sodium seed,At a temperature of 20 + - 5 &At a stirring rate of 30 r / min,Stirring for 50 minutes; c2, control temperature 20 ± 5 ,Acetone 2000 L was added dropwise over 90 to 120 minutes,After the dropwise addition, the crystal was incubated at a temperature of 20 ± 5 C for 60 minutes; c3, the crystal solution obtained in step c2 is subjected to centrifugal filtration in a centrifuge,After discharge,The filter cake was washed with 300 L of acetone,Washed twice,And then centrifuged for 180 minutes,After the cake from the packet crushing,Placed in a double cone vacuum dryer,At a temperature of 50 to 60 C,Vacuum 0.095mpa under the dry,So that the water is less than 4%The product cefotaxime sodium is obtained.The reaction yield (mass yield) of this synthetic method was 156.7,The obtained cefotaxime sodium product,Its content is 96.5%,The moisture content was 3.2%The residual amount of 7-ACA was 0.1%.
Acetonitrile 43.5g was added into a four-necked flask, 7.1g of mercaptotetrazole was added, 16g of 7-ACA was added and stirred uniformly. 63g of BF3-acetonitrile was added within 15 minutes, the temperature was raised to 35-39 C, and the reaction was stirred 50 ~ 60 minutes, cooled to an internal temperature of 28 ~ 32 . Within 15 minutes (hydrochloric acid 14.76g + water 12.6g) mixture was added, the temperature was maintained, stirred for 40 minutes, cooled to 10 ~ 20 C, Yang Jing crystal 1 hour.Suction filtration, with acetone 120ml 4 times top wash. 45 C for 15 hours under vacuum. (Before unloading moisture ? 1.0%) was 19.5g solid, molar yield 95.1%, purity 99.9%.
the 65g and boron second grade nitrile trifluoride 6.8g1-methyl-5-mercapto tetrazole mixing, stirring 30 min, then add 14g7-ACA, in 30 C reaction under 1h rear, turn to 100g purified water to hydrolyze, in 10 C lower, by adding dilute ammonia water to the crystal appeared, brilliantly last 30 min, continue adding dilute ammonia water to adjust pH to 3.0, nourishing crystal 1h rear, filtering, with the concentration of 60% acetone aqueous solution after washing, drying to moisture ? 1%, to get 16.1g white solid 7-ACT, its purity > 99%, yield of quality 115%;
15.9 g of compound I (0.1 mol, M.W. 159) and 28.49 g of compound II (0.11 mol, M.W. 259) were addedInto a reaction flask containing 3.18 g of dimethyl carbonate, stirred at 35 C for 1 hour, followed by the addition of 38.5 g of compound III(0.11 mol, M.W. 350), 3.18 g of PEG-800 was added with stirring, and after stirring for 10 minutes, 0.975 g of triethylamine was added,10 stirring reaction 4 hours, and then dropping 5w.t.% sodium hydroxide solution to pH = 7, by adding excessive acetone, precipitation of white knotCrystal, vacuum drying at 65 C to obtain 65.8 g of compound V (M.W.661), the yield of 99.5%, 99.99% purity, total miscellaneousLess than 0.01%.
With sulfuric acid; for 0.0666667h;Microwave irradiation;
The method for synthesizing cefpirome sulfuric acid by microwave method according to the present invention,Comprising the steps of:(1) 7-aminocephalosporanic acid (2.72 g, 7-ACA, Compound I, MW272, 0.01 mol) and AE-activity(AEMA, Compound VII, MW 350, 0.011 mol) was mixed and homogeneously ground.(Compound IV, MW 119, 0.011 mol) and concentrated sulfuric acid (10.88 g, 98% by weight) were added to the solution, followed by the addition of 2,30 g of 2,3-cyclopentenopyridine.(2) 300W microwave reaction for 1 minute,450W microwave reaction for 1 minute,750W microwave reaction for 2 minutes;(3) After completion of the reaction,The reaction residue was added to 29.92 g of deionized water,Mixing and filtering,Take filtrate,The solvent was removed,A white solid,50 & lt; 0 & gt; C for 4 hours under vacuum,That is to get the cefpirome sulfuric acid 5.09g (MW514),Yield 99.0%Purity 99.9% or more.
Stage #1: 2-thienylacetic acid chloride; 7-Aminocephalosporanic acid With triethylamine In water; ethyl acetate; acetone at 0 - 5℃; for 3h;
Stage #2: isonicotinamide With hydrogenchloride In water at 15℃; for 150h;
1
A process for the preparation of cephalonium from a one-step process of 7-aminocephalosporanic acid comprising the steps of1) adding 7-aminocephalosporanic acid in water at 0-5 ° C; the mass ratio of said 7-aminocephalosporanic acid to water is 1: 2;2) adjusting the pH of the solution in step 1) with triethylamine solution to be 5. 0;3) adding acetone to the solution obtained in step 2), then adding thiophene acetyl chloride and ethyl acetate, stirring the reaction at 0-5 ° C for 3 hours,The mass ratio of the 7-aminocephalosporanic acid, acetone, thiophenacetic acid chloride and ethyl acetate is 1: 8: 1.0: 10, and the pH value of the solution is maintained to be 6.0 by dropping triethylamine solution.4) After the reaction is completed, the mixture is allowed to stand, the layers are separated, and the aqueous phase is extracted twice with ethyl acetate.5) step 4) decolorizing and filtering the activated carbon in the water phase of the decarburizing tank;6) Adjust the concentration of 10% HC1 aqueous solution Step 5)The resulting filtrate had a pH of 5.0,Then the isonicotinamide is added to the filtrate and reacted at 15 ° C for 150 hours; the mass ratio of the 7-aminocephalosporanic acid to the isonicotinamide is 1: 0.5;7) the end of the reaction, the liquid cooling to 5 ° C below, more than 1 hour to support the crystal;8) filtering the material liquid obtained in step 7), washing the filter cake with water once, and then washing with acetone, finally drying the filter cake in vacuum,To obtain said cephalonium having a purity of 98.5% and a yield of 63%.
Stage #1: 7-Aminocephalosporanic acid With chloro-trimethyl-silane; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane for 12h; Reflux; Large scale;
Stage #2: With trimethylsilyl iodide; N,N-diethylaniline In dichloromethane at 18℃; for 3h; Large scale;
Stage #3: 5,6,7,8-tetrahydroquinoline In dichloromethane; N,N-dimethyl acetamide for 6h; Large scale;
1 Example 1: Synthesis 7-ACQ
dichloromethane 90KG (68L) + bis (trimethylsilyl) amine 19.5KG (25L) in 300L reaction vessel and stirred.Added 7-ACA25KG + trimethylchlorosilane 0.22KG (0.25L).Warmed to 58 ± 2 , stirred at reflux for 12 hours.Cooled to 5 ± 2 , added diethylaniline 25KG (27L), and mix well.Was added trimethylsilyl iodide 30KG (21.5L), stirred for 30 minutes.Warmed to 18 ± 2 , the reaction was stirred for 2.5 hours.Cooling to 8 ± 2 , tetrahydrofuran 4.5KG (5L), stirred for 30 minutes.Add tetrahydroquinoline 26KG (23L) + dimethylacetamide 47KG (50L), the reaction for 6 hours.The reaction was transferred into 500L reactor.Join dichloromethane 150KG (113L), and mix well.Cooled to 5 ± 2 , solution of isopropanol 25KG (32L).Petroleum ether was added dropwise 100KG (154L), stirred for 30 minutes.Filtered, washed with petroleum ether 20KG (30.5L) filtered three times to give a pale yellow solid.20wt% H was added to the 300L reaction vessel2SO460KG (55L).Was added to the pale yellow solid, 18 ± 2 under stirring to dissolve.Static stratification, from the aqueous phase.The solvent adding 20 water 5KG, stirred and extracted for 10 minutes.Still hierarchical, discard the solvent phase.The combined aqueous phase to the 300L reactor, cooled to 5 ± 2 , dropping 25% aqueous ammonia: 1st dropping 9KG (8L), seeded a little stirred crystallization 20 minutes; 2nd dropping 7KG (6.2L), stirred for 15 minutes crystallization; 3rd dropping 5KG (4.5L), stirred for 15 minutes crystallization;4th dropwise (about 3KG), adjusted pH = 2.9 ± 0.1, stirring was continued for 30 minutes crystallization; Solution of acetone 25KG (32L).Temperature 5 ± 2 , stirring raise grain for 1 hour.Filtered, washed with acetone 56KG (71L) + 20KG water mixture is washed and filtered.Then with acetone 20KG (25L) three times to wash the filter cake is set below 40 vacuum dried to give a pale yellow intermediate 7-ACQ35KG (relative to 7-ACA yield of about 1.4).
With ammonium hydroxide; penicillin G amidase; In water; at 20℃;pH 6.5 - 7;Enzymatic reaction;
In the flask placed 80 g of 7-ACA with stirring , then 1000 ml of deionized water was added, agitation was carried out and t with 8% aqueous ammonia adjusted pH of 7-ACA to dissolve and controlled temperature to 20 C. then placed 30 g penicillin g amidase and dropwise added 55 g <strong>[19432-68-9]Methyl 2-thienylacetate</strong> mean while with 8% aqueous ammonia controlling the pEta6.5 to 7.0 until no pH varitaions. The liquid chromatographic test showed that the 7-ACA residue was less than 1.0% in the end of the reaction. The filtrate was collected by filtration, and a small amount of deionized water was used to immobilize the enzyme; the filtrate was added to a stirred flask with a controlled temperature of 20 C and 20 g of immobilized cephalosporin C deacetylase was introduced to start the reaction meanwhile with 8% ammonia control pEta7.0 ~ 7.5 to pH for 3 minutes to not change in the end of the reaction. The filtrate was collected by filtration, the filtrate was stirred to decolorization with 5 g of activated carbon. After 20 minutes, filtration was carried out , then the filtrate was adjusted to pH 2.0 to 2.2 with 10% hydrochloric acid and then cooled to 10 C for 1 hour. The product was filtered and washed with a small amount of deionized water and dried in vacuo to give 100 g of product of 3-Desacetyl Cephalothin, Weight Yield 125% (Description: The yield here is the weight yield, can be more than 100%, will not affect the purity).
With acetonitrile boron trifluoride complex; In acetonitrile; at 30℃; for 2h;
(1) 1.5 L of acetonitrile, 300 g of 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooct-2-ene-2-carboxylic acid, 1.5 kg of 5-Mercapto-1- methyltetrazole, 1.4 L of Borontrifluoride / acetonitrile complex were mixed, then heated to 40 C, and rapidly stirred for 1 h. after completion of reaction, it was cooled to 2 C. The reaction solution was mixed with 2.25 L of purified water pre-cooled to 5 C and slowly stirred until the crystal was precipitated, then stir again for 30 min, add 10% ammonia to adjust the pH to 3.4, control the temperature to 0 ~ 5 C, and raise the crystal for 3h. Filtration carried out, then washed twice with 1.5L of acetone, and vacuum drying to obtain white crystalline powder (6R, 7R) -7-amino-3 [(Z) -2- (4- methylthiazole) -5- yl] Vinyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 324g
Stage #1: 5-methyl-1,2,3,4-tetrazole With sulfuric acid at 20℃; for 0.333333h;
Stage #2: 7-Aminocephalosporanic acid at 20℃;
1.1; 2.1; 3.1; 4.1; 2 Example 1
Step 1) Slowly add 3.03g of 5-methyltetrazole to 51mL of 60% H2SO4, stir at room temperature for 20min, add 8.17g of 7-ACA in three times, and add 15min between each addition. Stir the reaction for 1 to 1.5h at room temperatureAfter the reaction, the reaction mixture was slowly poured into 100 g of ice water, and extracted with dichloromethane (4 × 30 mL). The extract was washed with 40 mL of water, 40 mL (3%) of Na2CO3 was dissolved, and 40 mL of water was washed, and dried with anhydrous Na2SO4.The solvent was distilled off, and 7-MTCA 7.87 g was obtained by vacuum drying. The yield was 96.21%, the purity was 99.82%, and the 7-MTCA isomer impurity was 0.02%.
95%
With borane-THF In tetrahydrofuran at 55℃; for 6h;
2.1
Step (1), 40 g (0.478 mol) of pentamethyltetrazole and 151 g of BF3 tetrahydrofuran complex (1.1 mol) plusInto 1000mL of tetrahydrofuran,Another 100 g of 7-ACA (0.368 mol)The reaction temperature was controlled at 55 ° C for 6 hours,Dropping 750mL water 350mLDCM stirring liquid separation,The aqueous phase was adjusted to pH 2.8 with 10% aqueous ammonia,Crystallization gave 7-MTCA,Drying at 45 ° C for 8 h gave 103.5 g of product,Yield 95%Purity 99.5%Isomer impurities 0.03%Moisture 0.5%;
Stage #1: 7-Aminocephalosporanic acid With sulfuric acid; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane for 4h; Reflux; Large scale;
Stage #2: isonicotinamide Large scale; Further stages;
1 Example 1
As shown in Fig. 2, 8.0 kg 7-ACA was added to a 200 liter reaction tank,86.7 kg of dichloromethane,14.5 kg hexamethyldisilazane (HMDS) and29ml concentrated sulfuric acid as a starter,4 hours after the reflux reaction cooling the reaction tank cooling,9.38 kg of trimethylsilyl iodide (TMS-I) was added while maintaining at -5 to 0 ° C,After stirring for 3 hours, 3.74 kg isonicotinamide was added,Slowly warmed, refluxed for 2 hours, and then the reaction was cooled to 0 ° C,9.42 kg of methanol was added, stirred for 0.5 hours, 35.2 L of 6N hydrochloric acid was added,The temperature was raised to 20 ° C, stirred for 0.5 hour, the organic phase was further extracted with 10 kg of water,The combined aqueous phase, transferred to a 150L reaction tank,Cooled to 0 ~ 5 , 6L 6.6% aqueous hydrogen peroxide solution was added,Plus stirring for 10 minutes, filtered, the residue was filtered off washed with 5kg of water,Combined filter wash, add 3kg activated carbon stirring decolorization 1 hour,Filtered, washed with 5kg filter layer, the combined washings, acetone was added,Rejection filter, washed twice with acetone, dried under vacuum at 40 ,Get the target product 7-IACA 5.23kg, weight yield 65.4%The purity of 98.87%, 7-IACA obtained HPLC chromatogram shown in Figure 3.
With acetonitrile boron trifluoride complex In acetonitrile at 0 - 30℃; for 2h;
1
Condensation reaction conditions as in Example 2, after the completion of the condensation reaction,The reaction was cooled to 20 ° C and water was added, 105 g. The aqueous ammonia solution was added dropwise at a pH of 2.5. The temperature was lowered to 10 ° C. The mixture was stirred for 2 hours, filtered and washed with acetone to obtain wet product 7-ACTM.Wet product 7-ACTM was suspended in water and acetonitrile,Triethylamine 19.0g, dissolved cooled to -20 ,The remaining conditions are the same as in Example 2.Finally, white cefotiam hydrochloride hydrochloride crystalline powder 45.2g (HPLC purity 99.4%),The yield was 82.3%, lower than the product yield prepared in Example 2.The reason may be that some 7-ACTM residues in the condensation reaction mother liquor can not participate in the subsequent acylation reaction.
With boron trifluoride dimethyl carbonate complex; acetic acid; carbonic acid dimethyl ester at 45 - 50℃;
4 Example 4
120 ml of dimethyl carbonate, 40 g of 7-aminocephalosporanic acid, and 20 g of MTZ were added at room temperature. At the same temperature, add boron trifluoride-dimethyl carbonate complex 10g, glacial acetic acid 10g, temperature control 45-50 ° C timing reaction 1-2.0hr, then cool down to 20 ° C below the addition of pure water 300ml hydrolysis, then add 310ml three The methyl chloride was extracted for 10 min and layered. Then add activated carbon for desaturation for 20 min filtration. The filtrate was controlled to a temperature of 5 ° C or lower, triethylamine was added dropwise to adjust the pH 7.0-8.0, then ATC.HCL (Example 1-2) was added, and the reaction was timed at 5 ° C or less for 1-2.0 hr. After the reaction was completed, the reaction was added. Concentrated hydrochloric acid 60ml, then add activated carbon for 20min, filter, add 1400-1500ml of acetone to the filtrate, add crystal seed crystal, after the crystal is complete, add 500-600ml of acetone, drip the crystal for 1.0hr. The crude separation of cefotiam hydrochloride was obtained by centrifugation. High-pressure liquid phase purity 98.0%, yield 91%, color grade is less than yellow-green standard colorimetric liquid No. 3
18.82 g
With boron trifluoride; carbonic acid dimethyl ester; citric acid at 20 - 30℃; for 1h;
1.1
Add 60 mL of dimethyl carbonate to a 500 mL three-necked flask.Tannic acid 7.06g,Add 6.36 g of DMMT with stirring, and add 10.00 g of 7-ACA.Slowly adding boron trifluoride-dimethyl carbonate complex 34.82g,The temperature was controlled at 20 to 30 ° C, and after 1 h, the HPLC monitoring reaction was completed.Add 1.28 g of sodium dithionite and stir for 10 min to transfer to water.Add 80 mL of isopropanol, slowly add concentrated ammonia water to adjust the pH to 3.0.Control the dropping time 30~60min,The temperature was lowered to 0 to 10 ° C for 1 h.Pumping to obtain 18.82g of 7-ACMT wet product,The purity of HPLC was 99.4%.The maximum single impurity is 0.08%.
2-(2-amino-1,3-thiazol-4-yl)acetyl chloride hydrochloride[ No CAS ]
[ 957-68-6 ]
cefotiam dihydrochloride[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
86.4%
Stage #1: 1-[2-(dimethylamino)ethyl]-1,2-dihydro-5H-tetrazole-5-thione; 7-Aminocephalosporanic acid With acetonitrile boron trifluoride complex In acetonitrile at 0 - 30℃; for 2h;
Stage #2: 2-(2-amino-1,3-thiazol-4-yl)acetyl chloride hydrochloride In acetonitrile at -20℃; for 1h;
2
500 ml clean dry four reaction bottles,120 ml of acetonitrile was added,7-ACA 25 g (0.092 mol),DMMT 18.5 g (0.107 mol),Stirring suspension, cooling the bath to 0 ~ 5 ,130 g of boron trifluoride acetonitrile complex was added dropwise(Mass concentration 19%, 0.226mol) drop completed,Water bath warmed to 25 ~ 30 ° C for 2 hours,After the reaction was dropped 50 ml of purified water,10% aqueous sodium carbonate adjusted PH = 8.2, was clear and transparent reaction solution,Continue to cool to -20 ,24.5 g (0.115 mol) of ATC.HCl was added in portions,Incubated for 1 hour,After completion of the reaction, 60 ml of methylene chloride and 45 g of purified hydrochloric acid were added,Stirred for 10 minutes after stratification,Layered water warmed to 15 ~ 20 ,Add 650 ml of acetone, stir at 15 ~ 25 ° C for 2 hours,filter,Acetone wash,Drying in vacuo gave white cefotiam hydrochloride 47.5 g crystalline powder(HPLC purity 99.1%, moisture 6.0%, acetone 1.5%) in a yield of 86.4%.
Stage #1: 7-Aminocephalosporanic acid With sodium hydrogencarbonate In water at 0 - 35℃;
Stage #2: dichloroacethyl chloride In water at 0 - 5℃; for 0.5h;
1
(1) 10g of 7-ACA raw material was added to 100ml of water,Then add 9.25g sodium bicarbonate,30 ~ 35 under stirring for 1 ~ 2h dissolved,Cooled to 0 ~ 5 ,Temperature control dropping 8.14g dichloroacetyl chloride,After maintaining the reaction at 0 ~ 5 for 30min, the solution was adjusted to pH4.5 ~ 5.0 with 30wt% sodium hydroxide,0 ~ 5 Yang Jing 2 hours, filtered, the filter cake was washed with 15ml,The product was dried at 25-30 ° C to obtain 13.2 g of compound of formula (II)Product purity greater than 98%Molar yield: 93.6%.
Stage #1: N,O-bis-(trimethylsilyl)-acetamide; 7-Aminocephalosporanic acid In acetonitrile at 20℃; for 4h; Inert atmosphere;
Stage #2: trimethylsilyl iodide With N,N-diethylaniline In acetonitrile at 10 - 15℃; for 1h; Inert atmosphere;
Stage #3: sodium hexamethyldisilazane; triphenylphosphine Further stages;
1 Example 1
Under nitrogen protection,10.89 g (40 mmol) of 3-acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooctan-2-enecarboxylic acid, acetonitrile 100 mL, 46 mmolN,O-bistrimethylsilylacetamide(BSA) In a reaction bottle, the reaction was stirred at room temperature for 4 hours, 4 to 6 mL of N,N-diethylaniline, and 44 mmol of trimethylsilyl iodide (TMSI) were added dropwise and reacted at 10 to 15°C for 1 hour.11.02 g (42 mmol) of triphenylphosphine was added and the reaction was continued for 1 h. Sodium hexamethyldisilazide 7.34 g (40 mmol) was added and stirred at room temperature for 45 min. The organic layer was separated and washed with water, followed by washing with 20% w/w aqueous NaCl solution. Drying over anhydrous MgSO4 afforded 22.21 g of compound 3 in 89.8% yield.
89.6%
Stage #1: N,O-bis-(trimethylsilyl)-acetamide; 7-Aminocephalosporanic acid In acetonitrile at 20℃; for 4h; Inert atmosphere;
Stage #2: trimethylsilyl iodide With N,N-diethylaniline In acetonitrile at 10 - 15℃; for 1h; Inert atmosphere;
Stage #3: sodium hexamethyldisilazane; triphenylphosphine Further stages;
1.1 Example 1
Step 1) Under nitrogen protection,3-Acetoxymethyl-5-thio-7-amino-8-oxo-1-azabicyclooctan-2-ene-2-carboxylic acid 10.89 g (40 mmol),100 mL of acetonitrile and 46 mmol of N,O-bistrimethylsilylacetamide (BSA) were placed in the reaction flask and stirred for 4 hours at room temperature. 4 to 6 mL of N,N-diethylaniline and trimethylsilyl iodide (TMSI) were added dropwise. 44mmol, reacted at 10-15°C for 1h, added 11.02g (42mmol) of triphenylphosphine, continued the reaction for 1h, added sodium hexamethyldisilazide 7.34g (40mmol), stirred at room temperature for 45min, separated the organic layer and washed with water, Then it was washed with 20% w/w aqueous NaCl solution and dried over anhydrous MgSO 4 to obtain 22.16g of compound 3 with a yield of 89.6%.
With gamma-Al2O2-O22-Na+; zeolite In water at 20℃; for 2h; Large scale;
1; 2; 3; 4.1 Example 3 Synthesis of Cefuriofur Intermediate 7-Amino-3-[(2-furyl-carbonyl)-thiomethyl]-3-cephem-4-carboxylic acid
In a 500L reactor, 20kg of 7-aminocephalosporanic acid, 30kg of thiofurancarboxylic acid, 2kg of solid base catalyst γ-Al2O2-O22-Na+, 1kg of zeolite and 250kg of water were sequentially added, and the reaction was stirred at room temperature for 2 hours, filtered, and the filtrate was diluted with 6N hydrochloric acid. Adjust pHTo 6.5, filter, filter cake washed with white solid,Drying in vacuo gave 77.3 kg of 7-amino-3-[(2-furyl-carbonyl)-thiomethyl]-3-cephem-4-carboxylic acid.Yield 99.4%, purity 99.2% (HPLC)
99.1%
With solid base catalyst; zeolite In water at 20℃; for 2h; Large scale;
S1
S1: Put 20kg of 7-aminocephalosporanic acid, 30kg of thiofuranoic acid, 2kg of solid base catalyst, 1kg of zeolite and 250kg of water into a 500L reactor in turn, stir and react at room temperature for 2h, filter and adjust the pH to 5.5 with appropriate amount of 6N hydrochloric acid for the filtrate. Filter and wash the filter cake with water to obtain a white solid, which is dried in vacuum to obtain 37.1 kg of 7-amino-3-[(2-furanyl-carbonyl)-thiomethyl]-3 cephem-4-carboxylic acid, yield 99.1%
2-(2-aminothiazol-4-yl)acetic acid hydrochloride[ No CAS ]
cefotiam dihydrochloride monohydrate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
165.8 g
Stage #1: 2-(2-aminothiazol-4-yl)acetic acid hydrochloride With phosphorus trichloride In dichloromethane at -10℃; for 2h; Green chemistry;
Stage #2: 1-[2-(dimethylamino)ethyl]-1,2-dihydro-5H-tetrazole-5-thione; 7-Aminocephalosporanic acid at 10℃; for 0.166667h; Green chemistry; Further stages;
1.1; 1.2; 1.3; 1.4
(1) 200 ml of dichloromethane was added to the reactor three-necked flask, after cooling to -10 °C, add aminothiazole acetate hydrochloride, then add 38 g of phosphorus trichloride for 2 h, filter, dichloromethane Wash the white wet product for use; (2) In another reactor three-necked bottle, 250 ml of dimethyl carbonate was added, cooled to 10 °C, and slowly introduced into the BF3 gas 110 g (about 1.0 h) with stirring.Preparing a boron trifluoride dimethyl etherate solution for use; (3) Another dry three-necked flask was charged with 7-ACA 80g, 1-(2-dimethylaminoethyl)-5-mercaptotetrazole 40g, dimethyl carbonate 250ml, and stirred for 10min,Cooling to 10 ° C, adding boron trifluoride carbonate prepared aboveThe ester solution was heated to 50 °C for 1.0 h. After the reaction was completed, the reaction solution was cooled to 20 °C. 90 ml of n-butanol, EDTA-2Na 2 g and NaHSO3 4 g were added, 120 g of aqueous ammonia solution was added dropwise within 20 min, and the mixture was cooled to 15 °C with stirring reaction for 35min, crystallization, stirring for 3h, suction filtration, filter cake washed with acetone 200ml 3 times, to obtain milky white wet solids 205g; (4) take a three-neck bottle, add 350ml of deionized water and the wet product obtained in the previous step, stir for 15min, cool down to 0 °C, add 80ml of triethylamine, react until the solid is completely dissolved, add 120g of aminothiazole acetyl chloride to the solution After reacting for 2 hours, 280 ml of a solvent of dichloromethane and 50 g of concentrated hydrochloric acid gas were added to the reaction vessel, and the mixture was stirred for 15 minutes, and allowed to stand for stratification. 500 ml of acetone solvent was added to the solution to precipitate crystals, and 1500 ml of acetone was further added dropwise, and the crystals were crystallized for 2 hours, and suction filtered. The filter cake was washed with acetone solvent 400 ml, and dried under vacuum at 40 °C for 25 min to obtain cefotiam hydrochloride monohydrate white solid 165.8 g.
With boron trifluoride dimethyl carbonate complex; carbonic-acid; carbonic acid dimethyl ester; at 0 - 10℃; under 2.0 Torr;
11.81g (0.1mol) of <strong>[18686-82-3]2-mercapto-1,3,4-thiadiazole</strong>, BF3-dimethyl carbonate (0.25mol, calculated as BF3), 180ml of dimethyl carbonate, 0.1mol of carbonic acid were added to the reactor, and then 27.23g (0.1mol) of 7-ACA was slowly added dropwise, and the reaction temperature was controlled at 0-10 C for 2 h. After the reaction was completed, cold water was added, and the pH was adjusted to 5.5 by dropwise addition of ammonia water, and the crystal was crystallized for 1 h, and the crystal was maintained for 2-2.5 h. After centrifugation and drying, 31.54 g of Intermediate 1 was obtained, the yield was 95%, and the purity was 99.4%.
93%
With hydrogenchloride; boron trifluoride dimethyl carbonate complex; In dichloromethane; at 20 - 30℃;pH 3.5;Large scale;
Add <strong>[18686-82-3]2-mercapto-1,3,4-thiadiazole</strong>, BF3-dimethyl carbonate, 100 L of dichloromethane to Reactor A, slowly add 7-ACA, control the reaction temperature at 20-30 C, start the stirring device for stirring. The reaction is carried out for 5-6 h, and hydrochloric acid is added to adjust the pH to 3.5 during the reaction. After the reaction is completed, it is transferred to the aqueous phase.Adding sodium carbonate for crystallization, centrifuging, and drying to obtain Intermediate 1,
Stage #1: 1-[2-(dimethylamino)ethyl]-1,2-dihydro-5H-tetrazole-5-thione; 7-Aminocephalosporanic acid With boron trifluoride In acetonitrile; butan-1-ol at 0 - 5℃; for 1.5h;
Stage #2: With hydrogenchloride In water
Preparation of Compound II
51.97 g (0.3 mol) of 1-(2-dimethylaminoethyl)-1,2,3,4-tetrazol-5-thiol (DMMT),Boron trifluoride-acetonitrile (0.6 mol, calculated according to boron trifluoride), acetonitrile 200 ml,150ml of butanol was added to the reaction tank and the temperature was controlled at 0-5 °C.81.68 g (0.3 mol) of 7-ACA was slowly added dropwise, and the reaction was stirred at 0-5 ° C for 1.5 h.2M hydrochloric acid (0.6 mol) during the reaction, the reaction is finished.Then pass dry hydrogen chloride gas, crystallize with acetone, and centrifuge.Drying gave 114.72 g of compound II in a yield of 90% with a purity of 99.3%.
Under nitrogen protection,Add 100 mL of benzene to the reaction flask in turn,7-ACA 40mmol,48mmol hexamethyldisilazane,Pyridine 0.5 mmol,Stirring to reflux for 2 h,The reaction solution was cooled down to 0 C.Trimethylsilyl iodide (TMSI) 44 mmol was added dropwise.Insulation reaction for 1 h,Adding 38 mmol of trifluoroethoxy phosphate,Continue the reaction for 1 h, add 36 mmol of sodium hexamethyldisilazide, 60 mmol 15-crown-5,Heated back to reflux for 30 min,Cool to room temperature,Add <strong>[82294-70-0]4-methylthiazole-5-formaldehyde</strong> 38mmol,The reaction was carried out at room temperature for 6 h.The reaction is completed,Add 100 mL of methanol to precipitate a solid.Filter and wash with 50 mL THF.Drying under reduced pressure at 35 C gave 10.52 g of compound 4, the yield is 85.48%,The purity was 99.88%, and there was no E isomer.
Stage #1: 7-Aminocephalosporanic acid With pyridine; 1,1,1,3,3,3-hexamethyl-disilazane In benzene for 2h; Inert atmosphere; Reflux;
Stage #2: With trimethylsilyl iodide In benzene at 0℃; for 1h;
Stage #3: acetaldehyde Further stages;
1; 2; 3; 1; 2 Example 1: Synthesis of Compound 2
Under nitrogen protection, 100 mL of benzene, 7-ACA 40 mmol, 48 mmol of hexamethyldisilazane and pyridine 0.5 mmol were sequentially added to the reaction flask, and the mixture was stirred and heated to reflux for 2 h.The reaction solution was cooled to 0 ° C, and trimethylsilyl iodide (TMSI) 44 mmol was added dropwise.The reaction was kept for 1 h, and 38 mmol of trifluoroethoxy phosphate was added to continue the reaction for 1 h.Add 36 mmol of sodium hexamethyldisilazide, 60 mmol of 15-crown-5, and heat to reflux for 30 min.After cooling to room temperature, 36 mmol of acetaldehyde was added and the mixture was reacted at room temperature for 6 h. After completion of the reaction, 50 mL of water was added to the reaction solution, and the mixture was stirred, and the organic phase was collected, extracted with 3 mL of 3 mL/L hydrochloric acid, and the mixture was combined, washed with water, 50 mL of dichloromethane, and the organic layer was separated. The solution was adjusted to pH 2.5, and the solid was precipitated, filtered, washed with water and acetone, and dried under reduced pressure to give 7.30 g of Compound 2, yield 84.24%, purity 99.86%, and the reverse ratio was 97.4:2.5.
First, <strong>[18686-82-3]2-mercapto-1,3,4-thiadiazole</strong> 11.82g (0.1mol), dimethyl carbonate 120ml,BF3-dimethyl carbonate complex (0.3mol, calculated as BF3),0.05 mol of carbonic acid was added to the reactor to stir and dissolve.Further, 7-ACA 35.39 g (0.1 mol) was slowly added dropwise, and the reaction was controlled at 0-10 C.The reaction was stirred for 1 h, and after the reaction was completed, dry hydrogen chloride gas was introduced.Cool down to -5-0 C to precipitate crystals, centrifuge, and dry.The intermediate 1 was obtained as 35.39 g, the yield was 96%, and the purity was 99.5%.
With sodium hydrogencarbonate In water; acetone at 0℃; for 0.5h; Inert atmosphere;
81%
Stage #1: 7-Aminocephalosporanic acid With sodium hydrogencarbonate In water at 0 - 20℃; for 0.166667h;
Stage #2: acetic anhydride In water; acetone at 0℃; for 0.5h;
(6R,7R)-7-Acetam ido-3-(acetoxymethyl)-8-oxo-5-thia-1 -azabicyclo[4.2.O]oct-2-ene-2- carboxylic acid (26).
7-ACA (500 mg, 1.84 mmol) was suspended in H20 (8 mL), NaHCO3 (387 mg, 4.60 mmol) was added and the resulting mixture stirred at room temperature for 10 mm before being cooled to 000. Acetic anhydride (347 uL, 0.368 mmol) in acetone (10 mL) was added and the reaction stirred at 0 00 for 30 mm. Acetone was removed under reduced pressure, the resulting material was diluted in H20 and neutralised with satd NaHCO3 (aq). The aqueous solution was washed with EtOAc, acidified to pH 2 with 1 M HCI and extracted with EtOAc (x3). The organic layers were combined, washed with brine, dried over Na2SO4 and evaporated to afford the product as a colourless foam (471 mg, 81%). IR (solid): Vmax 3317, 2937, 1771, 1718, 1755, 1625, 1528, 1219 cm. 1H NMR (400 MHz, DMSO-d6) O 13.67 (brs, 1H), 8.84 (d, J= 8.4 Hz, 1H), 5.68 (dd, J= 8.3, 4.9 Hz, 1H), 5.08 (d, J= 4.9 Hz, 1H), 5.00 (d, J= 12.8 Hz, 1H), 4.68 (d, J= 12.8 Hz, 1H), 3.63 (d, J = 18.0 Hz, 1H), 3.48 (d, J= 18.1 Hz, 1H), 2.03 (5, 3H), 1.91 (5, 3H). 130 NMR (101 MHz, DMSO) δ 170.2, 170.1, 165.0, 162.9, 126.4, 123.4, 62.7, 59.0, 57.4, 22.1, 20.6. HRMS (ESl): calcd for C12H15N206S (M + H) 337.0470, found 337.0479.
With boron trifluoride diethyl etherate; acetic acid; at 5 - 10℃;
Boron trifluoride-dimethyl carbonate complex (2.5mol)Dissolved in 150ml of dimethyl carbonate,Add 132.26 g (1 mol) of compound II,Dissolve with stirring at room temperature,Control the temperature at 5-10 ,Add acetic acid (1mol),Then slowly add 7-ACA 299.49g (1.1mol),Controlled at 5-10 for 1-1.5h,Add hydrochloric acid solution (mass fraction 18%) to pH to 2.5 for crystallization,Filtered, washed with purified water,Vacuum drying to obtain compound III361.85g,Molar yield of 95%,The purity is 99.93%, and the maximum single impurity is 0.03%.
With aluminum (III) chloride; boron trifluoride; carbonic acid dimethyl ester; at 5 - 30℃; for 1h;
Step 1), add 272 g (1.0 mol) of 7-ACA, 1090 ml of dimethyl carbonate, 175 g (1.10 mol) of TTZ to the reaction flask, turn on the stirring, and lower the temperature of the reaction system to 5 C to 10 C. 9.4g of AlCl3-BF3-dimethyl carbonate solution [(wBF3) = 18%] (wherein, AlCl3 0.66g (0.005mol), BF3 1.7g (0.025mol)), after the dropwise addition is completed, the temperature is raised to 20-30 C Incubate for 1 h, add 1500 ml of purified water, add 135 mL of 2% sodium dithionite solution, stir for 1 h, adjust the pH to 2.5 with ammonia, cool to 10 C, suction filter, filter cake with acetonitrile / purified water = 1: 3 The mixed solution was rinsed twice with 100 ml and dried to obtain 347.9 g of 7-ACT, yield: 92%, purity 98.2%.
90%
With aluminum (III) chloride; boron trifluoride; carbonic acid dimethyl ester; at 5 - 30℃; for 1h;
Step 1), 7-ACA 100g (0.367mol), dimethyl carbonate 400ml, TTZ 64g (0.402mol) are added to the reaction flask, the stirring is started, the reaction system is cooled to 5 C to 10 C, and added dropwise to the reaction system 14.5g AlCl3-BF3-dimethyl carbonate solution [(wBF3) = 18%] (Among them, 1.0g (0.0075mol) of AlCl3, 2.6g (0.038mol) of BF3), after the dropwise addition was completed, the temperature was raised to 20 to 30 C. Incubate for 1h, add 750ml of purified water, dropwise add 50mL of 2% sodium dithionite solution, stir for 1h, adjust the pH to 3 4 with ammonia water, lower the temperature to 10 15 , suction filter, filter cake with acetonitrile / purified water = The mixed solution of 1: 3 was rinsed twice in 100 ml, and dried to obtain 125 g of 7-ACT, with a yield of 90% and a purity of 97.8%.
Stage #1: 7-Aminocephalosporanic acid With iodine; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane at 0 - 45℃; for 5h;
Stage #2: With trimethylsilyl iodide; triethylamine In dichloromethane at 0 - 10℃; for 4h;
Stage #3: 5,6,7,8-tetrahydroquinoline; toluene-4-sulfonic acid Further stages;
3
Put 27.2 g of 7-ACA into 150 ml of dichloromethane, lower the temperature to 0 to 5 ° C, and add 30 ml of N, N-hexamethyldisilazane and 0.1 g of iodine. The feed liquid was then heated to 45 ° C. and refluxed for 5 hours. The temperature of the feed liquid is lowered to 0-10 ° C, 15 ml of triethylamine and 40 g of trimethyliodosilane are added, and the reaction is kept for 4 hours. Then, 25 g of 5,6,7,8-tetrahydroquinoline was added to the feed liquid, and the reaction was held for 15 hours. Then, 800 ml of n-butane was added dropwise to the material solution, and a solid was gradually precipitated. After stirring for 60 minutes, filtration was performed, and an appropriate amount of n-butane was washed. Drain.The obtained solid is added to 120 ml of water, about 20 g of p-toluenesulfonic acid is added, the pH of the feed liquid is adjusted to about 3.0 to 3.5, and the solid is dissolved. Then, 5 g of activated carbon was added, the mixture was decolorized by stirring for 30 minutes, and then filtered. The obtained filtrate was added dropwise to 1200 ml of acetone, a solid was precipitated, stirred for 30 minutes, and filtered, washed with an appropriate amount of acetone, dried by suction, and dried in a vacuum drying box at 40 ° C. to obtain p-methylbenzenesulfonate of the compound represented by formula Approximately 22 g of acid salt, 95% product purity, molecular structure is as follows:
Stage #1: 7-Aminocephalosporanic acid With triethylamine In dichloromethane at 0 - 5℃; for 1h;
Stage #2: With chloro-trimethyl-silane In dichloromethane at 0 - 5℃; for 2.5h;
Stage #3: 5,6,7,8-tetrahydroquinoline Further stages;
1
Put 27.2g of 7-ACA into 150ml of dichloromethane and lower the temperature to 0 5 50 ml of triethylamine was added dropwise over 60 minutes. After the dropwise addition was completed, 27 g of trimethylchlorosilane was added dropwise to the feed solution. The dropwise addition was completed in 90 minutes. The temperature was maintained at 0-5 ° C for 60 minutes. The solids were removed by filtration and 50 ml was used. Wash with dichloromethane and combine the filtrates;(2) The combined filtrate was cooled to -10 to -5 ° C, 15 ml of triethylamine and 50 g of trimethyliodosilane were added, and the reaction was maintained at 0 to 10 ° C for 3 hours.(3) Then, 25 g of 5,6,7,8-tetrahydroquinoline was added to the feed liquid, and the reaction was held for 12 hours. Then, 800 ml of isopropanol was added dropwise to the material solution, and a solid was gradually precipitated. After stirring for 60 minutes, the mixture was filtered and washed with isopropanol. Drain.(4) The obtained solid was added to 100 ml of water, 30 ml of concentrated hydrochloric acid was added, the solid was dissolved, and then 5 g of activated carbon was added, and the mixture was decolorized by stirring for 30 minutes, and then filtered. The obtained filtrate was added dropwise to 1000 ml of isopropyl alcohol, a solid was precipitated, stirred for 30 minutes, and then filtered, washed with an appropriate amount of isopropyl alcohol, drained, and dried in a vacuum drying box at 40 ° C to obtain two compounds of the formula I The hydrochloride is about 28g, the purity of the product is 96%, and the molecular structure is as follows:
Stage #1: 7-Aminocephalosporanic acid With iodine; 1,1,1,3,3,3-hexamethyl-disilazane In dichloromethane at 0 - 45℃; for 5h;
Stage #2: With trimethylsilyl iodide; triethylamine In dichloromethane at 0 - 10℃; for 4h;
Stage #3: 5,6,7,8-tetrahydroquinoline Further stages;
2
Put 27.2g of 7-ACA into 150ml of dichloromethane and lower the temperature to 0 5 .30 ml of N, N-hexamethyldisilazane and 0.1 g of iodine were added, and then the feed liquid was heated to 45 ° C. and refluxed for 5 hours. The temperature of the feed liquid is lowered to 0-10 ° C, 15 ml of triethylamine and 40 g of trimethyliodosilane are added, and the reaction is kept for 4 hours.Then, 25 g of 5,6,7,8-tetrahydroquinoline was added to the feed liquid, and the reaction was held for 15 hours. Then, 800 ml of isopropanol was added dropwise to the material solution, and a solid was gradually precipitated. After stirring for 60 minutes, the mixture was filtered and washed with an appropriate amount of isopropanol. Drain. The obtained solid is added to 100 ml of water, about 10 ml of concentrated hydrochloric acid is added, the pH of the feed liquid is adjusted to about 3.5, and the solid is dissolved. Then, 5 g of activated carbon was added, the mixture was decolorized by stirring for 30 minutes, and then filtered. The obtained filtrate was added dropwise to 800 ml of acetone, a solid was precipitated, stirred for 30 minutes, and filtered, washed with an appropriate amount of acetone, dried by suction, and dried in a vacuum drying box at 40 ° C. to obtain a monohydrochloride salt of the compound of formula I 26g, product purity 96.8%, molecular structure is as follows:
Stage #1: 7-Aminocephalosporanic acid With N,O-bis-(trimethylsilyl)-acetamide In dichloromethane at 25 - 30℃; Inert atmosphere;
Stage #2: 2-thienylacetic acid chloride In dichloromethane at 10℃; for 1h; Inert atmosphere;
1.1-3.1
(1) In a 500ml reaction bottle,Put 7-ACA50g under nitrogen protection,Add 300ml of dichloromethane,N, O-bis (trimethylsilyl) acetamide (BSA) 53g,Stir to dissolve at 25-30 ,Cool down to 10 ,Add 33.1g of 2-thiophene acetyl chloride dropwise,Control drop addition for 60 minutes,The addition is complete,Insulation reaction 1-2h,Dichloromethane was distilled off under reduced pressure. After dichloromethane was evaporated, 300 ml of purified water was added, stirred rapidly, a solid was precipitated, filtered, and the product was washed twice with 200 ml of purified water. Reduced pressure and dried at 40 ° C. 67 g of white compound 2 were obtained. The yield was 92.0%.
85%
With N,O-bis-(trimethylsilyl)-acetamide In acetonitrile Inert atmosphere;
With tetrabutylammomium bromide; sodium hydrogencarbonate In dichloromethane; water at -5 - 0℃;
1.1; 2.1; 3.1; 1 Example 1
Step 1: In a 10 L four-neck round bottom flask, add 500 g of 7-aminocephalosporanic acid (7-ACA) and 5000 ml of dichloromethane.Add 170 g of a saturated aqueous solution of sodium bicarbonate and 5.0 g of tetrabutylammonium bromide under stirring,The temperature was controlled at -5 to 0 ° C, and 308 g of thiophene acetyl chloride was added dropwise, and the dropwise addition was controlled at 50 to 60 minutes. After holding the reaction for 4 hours, it was filtered, the filter cake was washed with dichloromethane, suction filtered, dried,Cephalotinic acid was obtained.
With sodium hydrogencarbonate In water at 15 - 30℃; for 1h;
1-6 Example 2
Add 10.0g (36.76mmol) of 7-ACA to a 250ml three-necked flask, add 120ml of water with stirring, heat to 25°C, add 7.0g of sodium bicarbonate (83.33mmol), stir until the solution is clear, cool to 15°C, add dropwise 6.0g 2-thiophene acetyl chloride (37.33mmol), react for 1h,Until the residual raw material is less than or equal to 1.0%, heat up to 30°C, add hydrochloric acid to adjust the pH to 1.52.0, filter,Obtain a wet product of cephalothin acid, then add 200ml of dichloromethane to dissolve it, separate the layers to remove the water, cool the lower organic layer to -90, add 40.0g (222.22mmol) of 30% sodium methoxide methanol solution, and first add 3.5g hypochlorite T-butyl ester (32.24mmol), then detect the residue of the raw material, calculate according to a certain method, add tert-butyl hypochlorite, add acetic acid, add sodium chloride solution, add dilute hydrochloric acid to control the pH 1.8-2.2, and let stand for Layer, the lower layer was concentrated to dryness, and 5.2 g (52.44 mmol) of cyclohexylamine was added, crystallized, filtered, rinsed with acetone, and dried.Obtained 17.5 g (33.30 mmol) of 7-α methoxed cefalotin cyclohexylamine salt. Based on 7-ACA, the molar yield is 90.66%.The impurity composition in the 7-α methoxed cefalotin cyclohexylamine salt is mainly 3-hydroxymethyl impurity, cefalotin acid raw material, bismethoxide R-type impurity, and bismethoxide S-type impurity, accounting for about 0.1% respectively. , 0.6%, 0.5%, 0.5%, purity 97.5%, white powder.
With sodium hydroxide In N,N-dimethyl-formamide at 20℃; for 2.5h;
1.2; 2.2; 3.2; 4.2; 1.2; 2.2; 3.2; 4.2; 5.2; 6.2; 7.2; 8.2
(2) To the filtrate A, add 2.92g of N, N-dimethylformamide, slowly add 10.88g of 7-ACA, dropwise add 30% sodium hydroxide solution to adjust the pH to 4.5, stir for 15min, and dropwise add 30% hydroxide Adjust the pH of the sodium solution to 4.5, stir for 15min, dropwise add 30% sodium hydroxide solution to adjust the pH to 4.5, control the room temperature to stir for 2h, monitor the reaction by HPLC, distill at 40 under reduced pressure, add 120mL of acetone for 1h, filter, 40 After vacuum drying for 4h, 17.04g of cefathiamidine was obtained, the yield was 90.2%, the purity by HPLC detection was 99.9%, and the maximum single impurity was 0.06%.
With palladium diacetate; sodium carbonate; triphenylphosphine; 1-hexyl-3-methylimidazolium tetrafluoroborate at 100℃; for 5h;
2
According to the method of Example 7 of CN104788471 B, 7-amino-3-[ (Z) -2- (4-methyl-5-thiazolyl) vinyl]-3-cephem-4-carboxylic acid (7- ATCA), specifically:In a 100mL three-necked flask, add 2.26g (10mmol) of 7-amino-3-vinyl-3-cephem-4-carboxylic acid and 2.2g (12mmol) of -methyl-5-bromothiazole , 1-methyl-3-hexylimidazole tetrafluoroborate ionic liquid 22.6g, palladium acetate 0.224g (1mmol), triphenylphosphine 0.26g (1mmol), sodium carbonate 1.1g(10mmol) was added to the reactor, reacted at 100C for 5h, the reaction was over, add saturated sodium bicarbonate solution, adjust pH = 8~10, the reaction solution was extracted 3 times with dichloromethane 5*3mL, the extract solution was anhydrous sodium sulfate Dry, concentrate, and recrystallize from ethanol to obtain 2.8 g of a light yellow solid product with a yield of 87% and a purity of 99%.
(6R,7R)-7-amino-8-oxo-3-((quinolin-8-ylthio)methyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
37%
Stage #1: thiooxine hydrochloride With sulfuric acid In acetonitrile
Stage #2: 7-Aminocephalosporanic acid In acetonitrile at 20℃; for 1.5h;
13 Intermediate 13a: (6R,7R)-7-amino-8-oxo-3-((quinolin-8-ylthio)methyl)-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Quinoline-8-thiol hydrochloride (134 mg, 0.68 mmol) is dissolved in dry acetonitrile (2 mL ). Sulfuric acid (500 mL , 8.8 mmol, 13 eq) is added dropwise resulting in a yellow precipitation that dissolves upon complete addition. Subsequently, 7-aminocephalosporanic acid (7-ACA, 188 mg, 0.69 mmol) is added and the mixture is stirred at room temperature for 90 minutes. TLC (5% methanol in DCM) indicates full consumption of Quinoline-8-thiol. The mixture is diluted with water (2 mL ) and the pH is adjusted to about 4 using 25% NH4OH resulting in a yellow precipitant. The product is filtered off, washed with water and acetone and dried yielding 93 mg (37%) of a light-brown powder, which was used directly in the next step without further purification.
Stage #1: furan-2-yl-oxo-acetaldehyde; 7-Aminocephalosporanic acid With tert.-butylhydroperoxide; C8H19Cl2OPPd In 2-methyltetrahydrofuran at 45℃; for 2.5h; Sealed tube; Inert atmosphere;
Stage #2: O-Methylhydroxylamin With Trimethylacetic acid In 2-methyltetrahydrofuran; water at 45℃; for 2.5h; Sealed tube; Inert atmosphere;
1-5 Example 1
In a 25mL reaction vessel, put the weighed PdCl2[(tBu)2P(OH)](5.0%mol) into it, seal it, and replace it with nitrogen 3 times; then, the 2-(2-furanyl)-2 -Oxo-acetaldehyde (1.2equiv.) and 7-aminocephalosporanic acid (0.2mmol, 1.0equiv.) were dissolved in 2-methyltetrahydrofuran (0.1M) except for the water, and then the solution was pumped into a sealed airtight Put the weighed tert-butanol peroxide (2.0equiv.) into the reaction vessel; stir well and react at 45 for 2.5 hours; then, put the weighed pivalic acid (5.0% mol) Put it into the reaction vessel, keep the temperature at 45°C, and then slowly drop the weighed 40%wt methoxyamine (2.0euqiv.) aqueous solution into the closed reaction vessel drop by drop for 2.5 hours; The residue of 7-aminosporanic acid was detected by high performance liquid chromatography. After the detection reaction, the system was cooled to room temperature; the organic phase was washed and extracted, and the target product was obtained by flash column chromatography. The stationary phase of the chromatography column It is silica gel, the mobile phase is a mixed solution of water and acetonitrile, and finally a white slurry of 3-decarbamoyl-acetyl-cefuroxime compound (90% wt) is obtained.