CN111320514A - Synthesis method of cefpodoxime D3 - Google Patents
Synthesis method of cefpodoxime D3 Download PDFInfo
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- WYUSVOMTXWRGEK-MWZKWMTOSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-(trideuteriomethoxyimino)acetyl]amino]-3-(methoxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@@H]1C(N2C(=C(COC)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC([2H])([2H])[2H])C1=CSC(N)=N1 WYUSVOMTXWRGEK-MWZKWMTOSA-N 0.000 title claims abstract description 23
- 238000001308 synthesis method Methods 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 24
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 16
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940125782 compound 2 Drugs 0.000 claims abstract description 14
- 229940126214 compound 3 Drugs 0.000 claims abstract description 14
- 229940125898 compound 5 Drugs 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 13
- INQOMBQAUSQDDS-BJUDXGSMSA-N iodomethane Chemical class I[11CH3] INQOMBQAUSQDDS-BJUDXGSMSA-N 0.000 claims abstract description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims abstract description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229940125904 compound 1 Drugs 0.000 claims abstract description 8
- AFZSMODLJJCVPP-UHFFFAOYSA-N dibenzothiazol-2-yl disulfide Chemical compound C1=CC=C2SC(SSC=3SC4=CC=CC=C4N=3)=NC2=C1 AFZSMODLJJCVPP-UHFFFAOYSA-N 0.000 claims abstract description 8
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 8
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- 238000007098 aminolysis reaction Methods 0.000 claims abstract description 3
- 238000006482 condensation reaction Methods 0.000 claims abstract description 3
- 238000003379 elimination reaction Methods 0.000 claims abstract description 3
- 150000002148 esters Chemical class 0.000 claims abstract description 3
- 238000005658 halogenation reaction Methods 0.000 claims abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 3
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 3
- 238000006467 substitution reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 58
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- 238000003756 stirring Methods 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 239000007810 chemical reaction solvent Substances 0.000 claims description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- 239000011259 mixed solution Substances 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 9
- 230000035484 reaction time Effects 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 7
- 239000001632 sodium acetate Substances 0.000 claims description 7
- 235000017281 sodium acetate Nutrition 0.000 claims description 7
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 4
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims description 2
- 239000012467 final product Substances 0.000 abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000007787 solid Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical group N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 229960005090 cefpodoxime Drugs 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 210000000959 ear middle Anatomy 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- JYVHOGDBFNJNMR-UHFFFAOYSA-N hexane;hydrate Chemical compound O.CCCCCC JYVHOGDBFNJNMR-UHFFFAOYSA-N 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 210000002741 palatine tonsil Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
- C07D277/593—Z being doubly bound oxygen or doubly bound nitrogen, which nitrogen is part of a possibly substituted oximino radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/05—Isotopically modified compounds, e.g. labelled
Abstract
The invention provides a method for synthesizing cefpodoxime D3, which comprises the following steps: 1) carrying out addition elimination reaction on the compound 1 and sodium nitrite to prepare a compound 2; 2) performing halogenation reaction on the compound 2 and liquid bromine to obtain a compound 3; 3) performing cyclization reaction on the compound 3 and thiourea to obtain a compound 4; 4) carrying out substitution reaction on the compound 4 and deuterated iodomethane to obtain a compound 5; 5) carrying out hydrolysis reaction on the compound 5 and sodium hydroxide to obtain a compound 6; 6) carrying out ester condensation reaction on the compound 6 and dibenzothiazyl disulfide to obtain a compound 7; 7) and carrying out aminolysis reaction on the compound 7 and the compound 8 to obtain the cefpodoxime D3. The invention adopts the commercially available deuterated iodomethane to synthesize the intermediate compound 6 for the first time, and further successfully synthesizes the cefpodoxime-D3 final product.
Description
Technical Field
The invention relates to a synthesis method of cefpodoxime D3, and belongs to the technical field of organic chemical synthesis.
Background
CefpodoximeThe molecular formula is C15H17N5O6S2The chemical name is (6R,7R) -7- [2- (2-amino-4-thiazolyl) - (Z) -2- (methoxyimino) acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0]Oct-2-ene-2-carboxylic acid. Cefpodoxime is clinically suitable for bronchitis and pneumonia caused by sensitive bacteria and infections of urinary system, skin, soft tissue, middle ear, tonsil and other parts.
The cefpodoxime-D3 is applied to clinical toxicological and pharmacological research. At present, no report document on the synthesis of isotopically labeled cefpodoxime-D3 is found.
The route of the existing cefpodoxime synthesis is as follows:
if the existing cefpodoxime method is adopted to synthesize cefpodoxime D3, the synthesis difficulty is that dimethyl sulfate is needed to be used for synthesizing an intermediate compound, but in the synthesis of deuterated cefpodoxime-D3, deuterated dimethyl sulfate is difficult to obtain.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provides a method for synthesizing cefpodoxime D3.
The technical scheme of the invention is as follows:
a method for synthesizing cefpodoxime D3, wherein the structure of cefpodoxime D3 is shown in formula I:
the synthetic route is as follows:
the method comprises the following steps:
the method comprises the following steps:
1) carrying out addition elimination reaction on the compound 1 and sodium nitrite to prepare a compound 2;
2) performing halogenation reaction on the compound 2 and liquid bromine to obtain a compound 3;
3) in the presence of sodium acetate, carrying out cyclization reaction on the compound 3 and thiourea to obtain a compound 4;
4) in the presence of potassium carbonate, carrying out substitution reaction on the compound 4 and deuterated iodomethane to obtain a compound 5;
5) carrying out hydrolysis reaction on the compound 5 and sodium hydroxide to obtain a compound 6;
6) carrying out ester condensation reaction on the compound 6 and dibenzothiazyl disulfide in the presence of triethylamine and triethyl phosphite to obtain a compound 7;
7) in the presence of triethylamine, carrying out aminolysis reaction on the compound 7 and the compound 8 to obtain cefpodoxime D3;
in the step 1), the reaction solvent is acetic acid, the reaction mode is that the reaction is carried out for half an hour by stirring in an ice bath, and then the reaction is carried out for 3 hours by heating to room temperature;
in the step 2), the reaction solvent is dichloromethane, the reaction temperature is room temperature, and the reaction time is 3 hours;
in the step 3), the reaction solvent is absolute ethyl alcohol, the reaction temperature is room temperature, and the reaction time is 18 hours;
in the step 4), the reaction solvent is acetone, and the reaction mode is reflux reaction for 3 hours;
in the step 5), the reaction solvent is absolute methanol, and the reaction mode is reflux reaction for 4 hours;
in the step 6), the reaction solvent is dichloromethane and anhydrous acetonitrile, the reaction temperature is room temperature, and the reaction time is 2 hours;
in the step 7), the reaction solvent is tetrahydrofuran, the reaction temperature is room temperature, and the reaction time is 2 hours.
Preferably
The method comprises the following steps:
1) adding the compound 1 and acetic acid into a reaction bottle, dropwise adding a mixed solution of sodium nitrite and water for half an hour under an ice bath condition, continuously stirring and reacting for half an hour under an ice bath condition, and then heating to room temperature for reacting for 3 hours to obtain a compound 2;
2) dissolving the compound 2 in dichloromethane, slowly adding liquid bromine dropwise under stirring at room temperature, and reacting at room temperature for 3 hours to obtain a compound 3;
3) suspending the compound 3, thiourea and sodium acetate in absolute ethyl alcohol, and stirring at room temperature for reacting for 18h to obtain a compound 4;
4) mixing the compound 4 and potassium carbonate in acetone, stirring and mixing uniformly, dropwise adding deuterated iodomethane at room temperature, and after completion, heating to reflux reaction for 3 hours to obtain a compound 5;
5) dissolving the compound 5 in anhydrous methanol, dropwise adding a mixed solution of sodium hydroxide and water under stirring at room temperature, and performing reflux reaction for 4 hours to obtain a compound 6;
6) sequentially adding the compound 6, dibenzothiazyl disulfide, anhydrous dichloromethane and anhydrous acetonitrile into a reaction bottle, slowly adding triethylamine under stirring at room temperature, stirring for 30 minutes, dropwise adding triethyl phosphite, and reacting at room temperature for 2 hours to obtain a compound 7;
7) and adding the compound 8 and water into a reaction bottle, adding triethylamine under ice-bath stirring, continuing to dropwise add a mixed solution of the compound 7 and tetrahydrofuran, and after the reaction is finished, heating to room temperature for reacting for 2 hours to obtain cefpodoxime D3.
More preferably still, the first and second liquid crystal compositions are,
in the step 1), the molar ratio of the compound 1 to the sodium nitrite is 1.35: 1;
in the step 2), the molar ratio of the compound 2 to the liquid bromine is 1: 1.21;
in the step 3), the mol ratio of the compound 3, thiourea and sodium acetate is 1: 1: 1.99;
in the step 4), the molar ratio of the compound 4, potassium carbonate and deuterated iodomethane is 1: 1.42: 1.35;
in the step 5), the molar ratio of the compound 5 to the sodium hydroxide is 1: 1.47;
in the step 6), the mol ratio of the compound 6, dibenzothiazyl disulfide, triethylamine and triethyl phosphite is 1: 1.38: 1.19: 1.50;
in the step 7), the mol ratio of the compound 8 to the triethylamine to the compound 7 is 1: 1.23: 1.33.
the invention has the following technical effects: the invention adopts the commercially available deuterated iodomethane to synthesize the intermediate compound 6 for the first time, and further successfully synthesizes the cefpodoxime-D3 final product.
Drawings
FIG. 1 is a HNMR map of cefpodoxime D3 prepared in example 1.
Detailed Description
Deuterated iodomethane was purchased from Cambridge Isotope Laboratories, inc.
Example 1
The synthesis method of cefpodoxime D3 comprises the following steps:
step 1)
The synthetic route is as follows:
adding the compound 1(12.5g, 107.6mmol) and acetic acid (30mL, 524.0mmol) into a 100mL three-neck flask, dropwise adding a mixed solution of sodium nitrite (5.5g, 79.7mmol) and 9 mL of water for half an hour under ice bath conditions, continuing stirring the reaction for half an hour under ice bath conditions, and then raising the temperature to room temperature for reaction for 3 hours. The reaction was monitored and after completion 150 ml of water was added, extracted with ethyl acetate (60 ml. times.3), the organic phases combined, washed once with water and saturated brine, dried and concentrated to give 15.0g of compound 2 as a yellow oil in 96% yield. Directly used for the next reaction.
Step 2)
The synthetic route is as follows:
compound 2(15.0g, 103.4mmol) was dissolved in 150 ml dichloromethane and liquid bromine (20g, 125.1mmol) was slowly added dropwise with stirring at room temperature, after completion, the reaction was carried out at room temperature for 3 hours, the reaction was monitored, after completion of the reaction, 150 ml water was slowly added, dichloromethane (100ml x3) was extracted, the organic phases were combined, washed once with water and saturated brine respectively, dried and concentrated to give 20.5g yellow oily compound 3, yield 89%, which was used directly in the next reaction.
Step 3)
The synthetic route is as follows:
suspending compound 3(20.0g, 89.3mmol), thiourea (6.8g, 89.3mmol) and sodium acetate (14.6g, 178.0mmol) in 120 ml of absolute ethyl alcohol, stirring at room temperature for reaction for 18h, monitoring the reaction, adding 200 ml of water under ice bath after the reaction is completed, precipitating a large amount of yellow solid, stirring for crystallization for 3 h, filtering, washing the filter cake with water and n-hexane for 1 time respectively, and drying to obtain 13.2g of yellow solid compound 4 with the yield of 73%.
Step 4)
The synthetic route is as follows:
compound 4(4.6g, 22.9mmol) and potassium carbonate (4.5g, 32.6mmol) are mixed in 100ml of acetone, stirred and mixed uniformly, deuterated iodomethane (4.5g, 31.0mmol) is added dropwise at room temperature, after completion, the temperature is raised to reflux reaction for 3 hours, the reaction is monitored, after the reaction is finished, the temperature is reduced to room temperature, 150 ml of water is added, ethyl acetate (100mlx3) is extracted, the organic phases are combined and washed once by water and saturated saline solution respectively, anhydrous sodium sulfate is dried, crude product column chromatography is carried out after concentration, 3.7g of yellow solid compound 5 is obtained, and the yield is 74%.
Step 5)
The synthetic route is as follows:
compound 5(3.7g, 17.0mmol) was dissolved in 20 ml of anhydrous methanol, and a mixed solution of sodium hydroxide (1.0g, 25mmol) and 15 ml of water was dropped under stirring at room temperature, after which the reaction was refluxed for 4 hours. Monitoring the reaction, after the reaction is completed, adjusting the pH of the reaction solution to 2-3 by using dilute hydrochloric acid in an ice bath, separating out a large amount of yellow solid, filtering, washing a filter cake by using water, and drying to obtain 2.7g of yellow solid compound 6 with the yield of 78%.
Step 6)
The synthetic route is as follows:
adding the compound 6(2.3g, 11.3mmol), dibenzothiazyl disulfide (5.2g, 15.6mmol), 6 ml of anhydrous dichloromethane and 12 ml of anhydrous acetonitrile into a 100ml three-necked flask in sequence, slowly adding triethylamine (1.36g, 13.4mmol) while stirring at room temperature, after stirring for 30 minutes, dropwise adding triethyl phosphite (2.8g, 16.9mmol), reacting for 2 hours at room temperature, monitoring the reaction, after the reaction is completed, adding 150 ml of water, extracting with ethyl acetate (100 ml. times.3), combining organic phases, washing with water and saturated saline water once respectively, drying and concentrating, and performing column chromatography to obtain 3.1g of yellow solid compound 7 with the yield of 77%.
Step 7)
The synthetic route is as follows:
adding a compound 8(1.4g, 5.7mmol) and 14 ml of water into a 100ml single-mouth bottle, adding triethylamine (713mg, 7.0mmol) under the stirring of an ice bath, then continuously dropwise adding a mixed solution of the compound 7(2.7g, 7.6mmol) and 14 ml of tetrahydrofuran, heating to room temperature for reaction for 2 hours after the completion of the reaction, monitoring the reaction, adding 15 ml of dichloromethane for back extraction after the reaction is completed, adjusting the pH of an aqueous phase to 2-3 by using dilute hydrochloric acid under the condition of the ice bath, precipitating a large amount of light yellow solid, filtering, washing a filter cake for several times by using dichloromethane, and drying to obtain 1.7g of light yellow final product, wherein the yield is 69%, M/z, M and M are obtained+＝431.0
The detection result of the prepared product is shown in fig. 1, and the product is cefpodoxime D3.
Claims (3)
1. A method for synthesizing cefpodoxime D3, wherein the structure of cefpodoxime D3 is shown in formula I:
the method is characterized in that the synthetic route is as follows:
the method comprises the following steps:
1) carrying out addition elimination reaction on the compound 1 and sodium nitrite to prepare a compound 2;
2) performing halogenation reaction on the compound 2 and liquid bromine to obtain a compound 3;
3) in the presence of sodium acetate, carrying out cyclization reaction on the compound 3 and thiourea to obtain a compound 4;
4) in the presence of potassium carbonate, carrying out substitution reaction on the compound 4 and deuterated iodomethane to obtain a compound 5;
5) carrying out hydrolysis reaction on the compound 5 and sodium hydroxide to obtain a compound 6;
6) carrying out ester condensation reaction on the compound 6 and dibenzothiazyl disulfide in the presence of triethylamine and triethyl phosphite to obtain a compound 7;
7) in the presence of triethylamine, carrying out aminolysis reaction on the compound 7 and the compound 8 to obtain cefpodoxime D3;
in the step 1), the reaction solvent is acetic acid, the reaction mode is that the reaction is carried out for half an hour by stirring in an ice bath, and then the reaction is carried out for 3 hours by heating to room temperature;
in the step 2), the reaction solvent is dichloromethane, the reaction temperature is room temperature, and the reaction time is 3 hours;
in the step 3), the reaction solvent is absolute ethyl alcohol, the reaction temperature is room temperature, and the reaction time is 18 hours;
in the step 4), the reaction solvent is acetone, and the reaction mode is reflux reaction for 3 hours;
in the step 5), the reaction solvent is absolute methanol, and the reaction mode is reflux reaction for 4 hours;
in the step 6), the reaction solvent is dichloromethane and anhydrous acetonitrile, the reaction temperature is room temperature, and the reaction time is 2 hours;
in the step 7), the reaction solvent is tetrahydrofuran, the reaction temperature is room temperature, and the reaction time is 2 hours.
2. The method of claim 1, wherein the method comprises the steps of:
1) adding the compound 1 and acetic acid into a reaction bottle, dropwise adding a mixed solution of sodium nitrite and water for half an hour under an ice bath condition, continuously stirring and reacting for half an hour under an ice bath condition, and then heating to room temperature for reacting for 3 hours to obtain a compound 2;
2) dissolving the compound 2 in dichloromethane, slowly adding liquid bromine dropwise under stirring at room temperature, and reacting at room temperature for 3 hours to obtain a compound 3;
3) suspending the compound 3, thiourea and sodium acetate in absolute ethyl alcohol, and stirring at room temperature for reacting for 18h to obtain a compound 4;
4) mixing the compound 4 and potassium carbonate in acetone, stirring and mixing uniformly, dropwise adding deuterated iodomethane at room temperature, and after completion, heating to reflux reaction for 3 hours to obtain a compound 5;
5) dissolving the compound 5 in anhydrous methanol, dropwise adding a mixed solution of sodium hydroxide and water under stirring at room temperature, and performing reflux reaction for 4 hours to obtain a compound 6;
6) sequentially adding the compound 6, dibenzothiazyl disulfide, anhydrous dichloromethane and anhydrous acetonitrile into a reaction bottle, slowly adding triethylamine under stirring at room temperature, stirring for 30 minutes, dropwise adding triethyl phosphite, and reacting at room temperature for 2 hours to obtain a compound 7;
7) and adding the compound 8 and water into a reaction bottle, adding triethylamine under ice-bath stirring, continuing to dropwise add a mixed solution of the compound 7 and tetrahydrofuran, and after the reaction is finished, heating to room temperature for reacting for 2 hours to obtain cefpodoxime D3.
3. The method according to claim 1 or 2,
in the step 1), the molar ratio of the compound 1 to the sodium nitrite is 1.35: 1;
in the step 2), the molar ratio of the compound 2 to the liquid bromine is 1: 1.21;
in the step 3), the mol ratio of the compound 3, thiourea and sodium acetate is 1: 1: 1.99;
in the step 4), the molar ratio of the compound 4, potassium carbonate and deuterated iodomethane is 1: 1.42: 1.35;
in the step 5), the molar ratio of the compound 5 to the sodium hydroxide is 1: 1.47;
in the step 6), the mol ratio of the compound 6, dibenzothiazyl disulfide, triethylamine and triethyl phosphite is 1: 1.38: 1.19: 1.50;
in the step 7), the mol ratio of the compound 8 to the triethylamine to the compound 7 is 1: 1.23: 1.33.
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| WO2000068234A2 (en) * | 1999-05-07 | 2000-11-16 | Ranbaxy Laboratories Limited | Process for the preparation of cefpodoxime acid |
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