CN112979704A - Voriconazole phosphocholine inner salt key intermediate and preparation method thereof - Google Patents
Voriconazole phosphocholine inner salt key intermediate and preparation method thereof Download PDFInfo
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- CN112979704A CN112979704A CN202110255862.9A CN202110255862A CN112979704A CN 112979704 A CN112979704 A CN 112979704A CN 202110255862 A CN202110255862 A CN 202110255862A CN 112979704 A CN112979704 A CN 112979704A
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- voriconazole
- phosphocholine
- inner salt
- key intermediate
- choline
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- 229960004740 voriconazole Drugs 0.000 title claims abstract description 71
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 title claims abstract description 57
- 150000003839 salts Chemical class 0.000 title claims abstract description 45
- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- YHHSONZFOIEMCP-UHFFFAOYSA-O phosphocholine Chemical compound C[N+](C)(C)CCOP(O)(O)=O YHHSONZFOIEMCP-UHFFFAOYSA-O 0.000 title claims abstract description 31
- -1 diisopropylamino Chemical group 0.000 claims abstract description 29
- 238000000034 method Methods 0.000 claims abstract description 28
- 229960001231 choline Drugs 0.000 claims abstract description 16
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007858 starting material Substances 0.000 claims abstract description 12
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229910052698 phosphorus Inorganic materials 0.000 claims abstract description 5
- 239000011574 phosphorus Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 53
- 238000006243 chemical reaction Methods 0.000 claims description 35
- 238000009833 condensation Methods 0.000 claims description 23
- 230000005494 condensation Effects 0.000 claims description 23
- 239000001763 2-hydroxyethyl(trimethyl)azanium Substances 0.000 claims description 21
- 235000019743 Choline chloride Nutrition 0.000 claims description 21
- SGMZJAMFUVOLNK-UHFFFAOYSA-M choline chloride Chemical group [Cl-].C[N+](C)(C)CCO SGMZJAMFUVOLNK-UHFFFAOYSA-M 0.000 claims description 21
- 229960003178 choline chloride Drugs 0.000 claims description 21
- 239000003153 chemical reaction reagent Substances 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 5
- 239000011230 binding agent Substances 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- OFCZCLMYSLREBG-UHFFFAOYSA-N C(C)(C)P(Cl)(OCCC#N)(N)C(C)C Chemical compound C(C)(C)P(Cl)(OCCC#N)(N)C(C)C OFCZCLMYSLREBG-UHFFFAOYSA-N 0.000 claims description 4
- 239000007810 chemical reaction solvent Substances 0.000 claims description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 claims description 4
- 229940011051 isopropyl acetate Drugs 0.000 claims description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 150000004820 halides Chemical class 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 150000007530 organic bases Chemical group 0.000 claims description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 2
- 150000001450 anions Chemical class 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims 1
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims 1
- 229960003865 tazobactam Drugs 0.000 claims 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 5
- 239000006227 byproduct Substances 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 3
- 238000012824 chemical production Methods 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 229950004354 phosphorylcholine Drugs 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- 239000002808 molecular sieve Substances 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 238000001816 cooling Methods 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 3
- 125000001731 2-cyanoethyl group Chemical group [H]C([H])(*)C([H])([H])C#N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- 238000010907 mechanical stirring Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 150000008301 phosphite esters Chemical class 0.000 description 2
- 150000003017 phosphorus Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- ZSJQVOIPLQDHCE-UHFFFAOYSA-N 3-dichlorophosphanyloxypropanenitrile Chemical compound ClP(Cl)OCCC#N ZSJQVOIPLQDHCE-UHFFFAOYSA-N 0.000 description 1
- UHPMCKVQTMMPCG-UHFFFAOYSA-N 5,8-dihydroxy-2-methoxy-6-methyl-7-(2-oxopropyl)naphthalene-1,4-dione Chemical compound CC1=C(CC(C)=O)C(O)=C2C(=O)C(OC)=CC(=O)C2=C1O UHPMCKVQTMMPCG-UHFFFAOYSA-N 0.000 description 1
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 1
- 206010007269 Carcinogenicity Diseases 0.000 description 1
- 241000223218 Fusarium Species 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010029155 Nephropathy toxic Diseases 0.000 description 1
- 241000235645 Pichia kudriavzevii Species 0.000 description 1
- 206010042938 Systemic candida Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 208000017773 candidemia Diseases 0.000 description 1
- 231100000260 carcinogenicity Toxicity 0.000 description 1
- 230000007670 carcinogenicity Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
- 229960004884 fluconazole Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 201000009085 invasive aspergillosis Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007694 nephrotoxicity Effects 0.000 description 1
- 231100000417 nephrotoxicity Toxicity 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- OJMIONKXNSYLSR-UHFFFAOYSA-N phosphorous acid Chemical compound OP(O)O OJMIONKXNSYLSR-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
- C07F9/6518—Five-membered rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the field of pharmaceutical chemical production, and discloses a key intermediate of voriconazole phosphocholine inner salt and a preparation method thereof, wherein the preparation method comprises the following two methods: the method A comprises the steps of taking ionized choline as a starting material, and then reacting the ionized choline with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt; or the method B, taking bis (diisopropylamino) 2 cyanoethoxylation phosphorus as a starting material, then reacting with voriconazole, and condensing with ionized choline to obtain the key intermediate II of the voriconazole phosphocholine inner salt. The method has the advantages of short synthetic route, simple operation, obvious inhibition of by-products, high product purity and suitability for industrial production.
Description
Technical Field
The invention relates to the field of pharmaceutical chemical production, and particularly relates to a key intermediate of voriconazole phosphocholine inner salt and a preparation method thereof.
Background
Voriconazole is a broad-spectrum triazole antifungal drug with the following indications: invasive aspergillosis; candidemia in non-neutropenic patients; severe invasive infections caused by fluconazole-resistant candida species (including candida krusei); severe infections caused by podophyllotoxins and fusarium. Primarily for the treatment of patients suffering from progressive, potentially life-threatening infections.
Due to poor water solubility of voriconazole, hydroxypropyl beta-cyclodextrin is required to be wrapped to increase solubility during injection preparation, and the preparation difficulty is high. In addition, hydroxypropyl beta-cyclodextrin has a good solubilizing effect on various insoluble drugs, but documents show that the auxiliary material has certain hemolysis, nephrotoxicity and carcinogenicity, other unidentified toxic and side effects possibly exist, and hydroxypropyl beta-cyclodextrin is used in a few preparations (such as drugs for treating severe infection and tumors) which are on the market and have special indications abroad. Therefore, intensive research and observation should be continued on such an adjuvant, and it should not be widely used as a conventional adjuvant in injections.
Chinese patent application No. CN201410224332.8 discloses a method for preparing high-purity voriconazole phosphate, which mainly comprises the following steps: (1) dissolving voriconazole and organic weak base in an organic solvent, dropwise adding a phosphorus trichloride solution, and stirring at room temperature for reaction after dropwise adding; (2) cooling the reaction system obtained in the previous step, hydrolyzing the ice-water mixture, and evaporating the organic solution after hydrolysis to obtain an intermediate conazole phosphite ester; (3) dissolving crude voriconazole phosphite and inorganic weak base in water, dropwise adding an oxidant aqueous solution, stirring in an ice bath for reaction, filtering, adjusting the pH value of the filtrate until a large amount of solid is separated out, and filtering to obtain the solid, namely the high-purity voriconazole phosphate. The acidic voriconazole phosphate compound is prepared by the method to increase the solubility of voriconazole, but the preparation needs to be prepared into salt for reuse when being subsequently prepared into an injection preparation, which brings inconvenience to the preparation of voriconazole into the injection preparation.
Disclosure of Invention
In view of the above-mentioned deficiencies in the prior art, the first object of the present invention is to provide a method for preparing a key intermediate of voriconazole phosphocholine inner salt, which has stable and reliable process, safe production, simple operation, capability of significantly inhibiting byproducts, and suitability for industrial production.
The second purpose of the invention is to provide a key intermediate of voriconazole phosphorylcholine ester inner salt prepared by the method, the aqueous solution is near neutral, so that the later-stage preparation of voriconazole phosphorylcholine ester inner salt is more uniform, the solubility of voriconazole phosphorylcholine ester inner salt is obviously improved, and the difficulty of the finished product preparation is reduced.
In order to achieve the above purpose, the solution adopted by the invention is as follows:
a key intermediate of voriconazole phosphocholine inner salt is shown as the following formula:
a preparation method of a key intermediate II of voriconazole phosphocholine inner salt comprises the following two main methods:
A. one of them includes: taking ionized choline as a starting material, and then reacting the ionized choline with voriconazole to obtain a key intermediate of voriconazole phosphocholine inner salt shown in a formula II;
B. the second group comprises: the method comprises the steps of synthesizing an intermediate III by taking bis (diisopropylamino) 2 cyanoethoxylation phosphorus as a starting material, reacting with voriconazole, and condensing with ionized choline to obtain a key intermediate II of voriconazole phosphocholine inner salt.
Wherein, the anion of the ionized choline is one of halide, sulfate radical, methanesulfonate radical, benzenesulfonate radical or p-toluenesulfonate radical; the halide ions are: chloride, bromide or iodide, preferably the ionized choline is choline chloride.
In the first general method a, the following two preparation methods a1 and a2 are included:
a1, comprising the following steps: choline chloride is used as a starting material to synthesize choline chloride phosphoester 2 cyanoethyl chloride, and then the choline chloride phosphoester 2 cyanoethyl chloride reacts with voriconazole to obtain a key intermediate of voriconazole phosphocholine inner salt shown in a formula II, wherein the reaction formula is as follows:
a2, comprising the following steps: choline chloride is used as a starting material to react with (diisopropyl) amino 2 cyanoethoxy phosphorus chloride, a condensation reagent shown in a formula III is synthesized under the action of an acid-binding agent, and then the condensation reagent reacts with voriconazole to obtain a key intermediate of voriconazole phosphocholine inner salt shown in a formula II, wherein the reaction formula is as follows:
in A2, the acid-binding agent is an organic base or an inorganic base; the organic base is: triethylamine or DIPEA; the inorganic base is as follows: ammonia or sodium carbonate.
In A2, in the process of obtaining the condensation reagent III from choline chloride, the reaction temperature is controlled to be-10 ℃ to 40 ℃, the reaction time is 1 to 12 hours, and the reaction solvent is as follows: dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-ether or toluene.
In A2, in the process of obtaining a key intermediate II of voriconazole phosphocholine inner salt by a condensation reagent III, reacting under the action of 1H-tetrazole, controlling the reaction temperature to be-10-70 ℃, the reaction time to be 1-16 hours, and the reaction solvent is: dichloromethane, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-ether or toluene.
In the second general method B, bis (diisopropylamino) 2 cyanoethoxylated phosphorus is used as a starting material, and then reacted with voriconazole, and then condensed with ionized choline to obtain a key intermediate II of voriconazole phosphocholine inner salt, wherein the synthesis process is as follows:
the invention has the beneficial effects that:
1. the method takes the ionized choline as the starting material, and then reacts with voriconazole to prepare the target product, namely the key intermediate of voriconazole phosphocholine inner salt, and the preparation process is stable and reliable; the whole synthesis route is short, the operation is simple, the generation of byproducts can be obviously inhibited, the environment is not polluted too much, and the method is suitable for large-scale industrial production.
2. The method has the advantages of good synthesis reaction selectivity, higher conversion rate, low raw material cost and high purity of the key intermediate of the voriconazole phosphocholine inner salt.
3. The aqueous solution of the key intermediate of voriconazole phosphorylcholine ester inner salt obtained by the invention is near neutral, so that the later-stage preparation of voriconazole phosphorylcholine ester inner salt is more uniform, the solubility of voriconazole phosphorylcholine ester inner salt is obviously improved, and the difficulty of the finished product preparation is reduced.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The key intermediate of voriconazole phosphorylcholine ester inner salt and the preparation method thereof provided by the embodiment of the invention are specifically explained below.
Example 1: preparation of key intermediate II of voriconazole phosphocholine inner salt
Choline chloride is used as an initial raw material to synthesize choline chloride phosphoester 2 cyanoethyl ester, and then the choline chloride phosphoester 2 cyanoethyl ester reacts with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt, which comprises the following specific steps:
1) condensing reagent choline chloride phosphite chloride 2 cyanoethyl ester:
keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 600ml of DCM, 279.3g (2.00mol) of choline chloride and 344.0g (2.00mol) of 2-cyanoethyl dichlorophosphite into a 3000ml reaction bottle, stirring for 1.5 hours, cooling to-5 ℃, slowly dropwise adding 212.5g (2.10mol) of triethylamine, keeping the temperature at-5-0 ℃ for reaction for 6 hours after dropwise adding is finished, and keeping the solution for later use.
2) Preparation of condensation intermediate II:
174.7g (0.50mol) of voriconazole, 35.0g (0.50mol) of 1H-tetrazole and 450ml of dry tetrahydrofuran are added into a 3000ml four-mouth reaction bottle, 174.7g of 4A molecular sieve is added, the temperature is reduced to 0 ℃, the corresponding DCM solution of 151.4g (0.55mol) of the prepared condensation reagent choline chloride phosphite chloride ester 2 cyanoethyl ester is added dropwise under mechanical stirring, the dropwise adding temperature is controlled to be between-3 ℃ and 3 ℃, after the dropwise adding is finished, the temperature is kept at about 0 ℃ for reaction for 3.5 hours, and then the temperature is increased to 25 ℃ for reaction for 8 hours. After the reaction, the molecular sieve was filtered off, the solution was quenched by adding 550ml of water, stirred for 2 hours, then allowed to stand for 1 hour, separated, and extracted by adding 430ml of × 3 dichloromethane to the aqueous phase. The dichloromethane layers were combined, washed with 250g × 3 water, and then the dichloromethane layer was dried over anhydrous sodium sulfate, filtered with suction, and the organic solvent was evaporated to give 283.5g of condensation intermediate II, 96.4% molar yield, and 94.8% HPLC purity. 1H-NMR (400MHz, DCCl3) < delta > 8.98(s,1H), < delta > 8.76(d,1H), < delta > 8.15(s,1H), < delta > 7.84(s,1H), < delta > 7.38(m,1H), < delta > 6.81 to 6.87(m,2H), < 5.12(d,1H), < 4.86 to 4.78(m,2H), < 4.51(d,1H), < 4.17 to 4.12(m,1H), < 4.08 to 3.95(m,2H), < 3.88 to 3.80(m,1H), < 3.49 to 3.45(m,1H), < 3.29(s,9H), < 2.71 to 2.66(m,1H), < 2.11 to 2.07(m,1H), < 1.31(d, 3H); ESI + MS: 552.21.
Example 2: preparation of key intermediate II of voriconazole phosphocholine inner salt
2.1 preparation of condensation reagent III:
choline chloride is used as an initial raw material to react with (diisopropyl) amino 2 cyanoethoxy phosphorus chloride, and a condensation reagent III is synthesized under the action of an acid-binding agent:
keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 500ml of DCM, 279.3g (2.00mol) of choline chloride and 222.6g (2.20mol) of triethylamine into a 3000ml reaction bottle, stirring for 0.5 hour, cooling to-5 ℃, slowly dropwise adding 473.4g (2.00mol) of 5 (diisopropyl) amino 2 cyanoethoxy phosphorus chloride dissolved in 500ml of DCM, after dropwise adding, keeping the temperature at-5-0 ℃ for reaction for 5 hours to obtain a condensation reagent III.
2.2 preparation of key intermediate II of Voriconazole phosphocholine ester inner salt
The condensation reagent III reacts with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt
174.7g (0.50mol) of voriconazole, 35.0g (0.50mol) of 1H-tetrazole and 500ml of acetonitrile are added into a 3000ml four-mouth reaction bottle, 174.7g of 4A molecular sieve is added, the temperature is reduced to 0 ℃, the mixture is stirred and dissolved, 339.9g (1.00mol) of corresponding DCM solution of the condensation reagent III prepared in the example 1 is dripped, the dripping temperature is controlled to be between-5 ℃ and 5 ℃, the temperature is kept at about 0 ℃ for reaction for 4 hours after the dripping is finished, and then the temperature is increased to 25 ℃ for reaction for 6 hours. After the reaction, the molecular sieve is filtered out, the solution is added with 500ml of water for quenching, stirred for 2 hours, then kept stand for 1 hour, separated, and added with 400ml of multiplied by 3 dichloromethane for extraction. The dichloromethane layers were combined, washed with 200g × 3 water, then the dichloromethane layer was dried over anhydrous sodium sulfate, filtered under suction, and the organic solvent was evaporated off to give 265.3g of condensation intermediate II, 90.2% molar yield, 97.0% purity by HPLC.
1H-NMR(400MHz,DCCl3):δ8.98(s,1H),8.76(d,1H),8.15(s,1H),7.84(s,1H),7.38(m,1H),6.81～6.87(m,2H),5.12(d,1H),4.86～4.78(m,2H),4.51(d,1H),4.17～4.12(m,1H),4.08～3.95(m,2H),3.88～3.80(m,1H),3.49～3.45(m,1H),3.29(s,9H),2.71～2.66(m,1H),2.11～2.07(m,1H),1.31(d,3H)；ESI+MS:552.21。
Example 3: preparation of key intermediate II of voriconazole phosphocholine inner salt
The method takes bis (diisopropylamino) 2 cyanoethoxylation phosphorus as a starting material, then the starting material reacts with voriconazole, and then the intermediate II is obtained by condensation with ionized choline, and the technical process is as follows:
1) condensation reagent bis (diisopropylamino) 2 cyanoethoxylated phosphorus:
keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 600ml DCM, 404.8g (2.00mol) of diisopropylamine and 344.0g (2.00mol) of dichloro 2-cyano ethyl phosphite into a 3000ml reaction bottle, stirring for 1.0 hour, cooling to 0 ℃, slowly dripping 222.6g (2.20mol) of triethylamine, reacting for 6 hours at-5-0 ℃ after dripping is finished, and keeping the temperature at the end of reaction for standby.
2) Preparation of condensation intermediate II:
174.7g (0.50mol) of voriconazole, 35.0g (0.50mol) of 1H-tetrazole and 450ml of dry tetrahydrofuran are added into a 3000ml four-mouth reaction bottle, 174.7g of a 3A molecular sieve is added, the temperature is reduced to 0 ℃, the corresponding DCM solution of 180.8g (0.60mol) of the prepared condensation reagent of bis (diisopropylamino) 2 cyanoethoxylation phosphorus is added dropwise under mechanical stirring, the dropwise adding temperature is controlled between-3 ℃ and 3 ℃, after the dropwise adding is finished, the temperature is kept at about 0 ℃ for reaction for 3.5 hours, and then the temperature is increased to 25 ℃ for reaction for 8 hours. After the reaction, the molecular sieve was filtered off, the solution was quenched by adding 550ml of water, stirred for 2 hours, then allowed to stand for 1 hour, separated, and extracted by adding 430ml of × 3 dichloromethane to the aqueous phase. The dichloromethane layers are combined, washed by 250g multiplied by 3 water, then the dichloromethane layer is dried by anhydrous sodium sulfate, filtered by suction and the organic solvent is removed by evaporation; keeping the temperature at about 0 ℃, introducing nitrogen for protection, adding 1200ml of THF and 139.7g (1.00mol) of choline chloride into a 3000ml reaction bottle, stirring for 4.5 hours, then heating to 45 ℃, keeping the temperature for reaction for 6 hours, sampling and controlling the reaction, obtaining a condensation intermediate II THF solution after the reaction is finished, obtaining 285.4g of condensation intermediate, wherein the molar yield is 86.6 percent, and the HPLC purity is 96.1 percent. 1H-NMR (400MHz, DCCl3) < delta > 8.98(s,1H), < delta > 8.76(d,1H), < delta > 8.15(s,1H), < delta > 7.84(s,1H), < delta > 7.38(m,1H), < delta > 6.81 to 6.87(m,2H), < 5.12(d,1H), < 4.86 to 4.78(m,2H), < 4.51(d,1H), < 4.17 to 4.12(m,1H), < 4.08 to 3.95(m,2H), < 3.88 to 3.80(m,1H), < 3.49 to 3.45(m,1H), < 3.29(s,9H), < 2.71 to 2.66(m,1H), < 2.11 to 2.07(m,1H), < 1.31(d, 3H); ESI + MS: 552.21.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A key intermediate of voriconazole phosphocholine inner salt is characterized by being shown as the following formula:
2. a process for preparing voriconazole phosphocholine inner salt key intermediate as claimed in claim 1, which comprises the following two processes:
the method A comprises the steps of taking ionized choline as a starting material, and then reacting the ionized choline with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt;
or the method B, taking bis (diisopropylamino) 2 cyanoethoxylation phosphorus as a starting material, then reacting with voriconazole, and condensing with ionized choline to obtain the key intermediate II of the voriconazole phosphocholine inner salt.
3. The method for preparing voriconazole phosphocholine inner salt key intermediate as claimed in claim 2, wherein the anion of the ionized choline is one of halide, sulfate, methanesulfonate, benzenesulfonate or p-toluenesulfonate.
4. The preparation method of key intermediate of voriconazole phosphocholine ester inner salt according to claim 3, wherein the halide is: chloride, bromide, or iodide.
5. The method for preparing key intermediate of voriconazole phosphocholine ester inner salt according to claim 4, wherein the ionized choline is choline chloride.
6. The preparation method of key intermediate of voriconazole phosphocholine ester inner salt according to claim 5, wherein method A comprises the following steps:
choline chloride is used as an initial raw material to synthesize choline chloride phosphoester 2 cyanoethyl ester, and then the choline chloride phosphoester 2 cyanoethyl ester reacts with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt, wherein the reaction formula is as follows:
7. the preparation method of key intermediate of voriconazole phosphocholine ester inner salt according to claim 5, wherein method A comprises the following steps:
choline chloride is used as an initial raw material to react with (diisopropyl) amino 2 cyanoethoxy phosphorus chloride, a condensation reagent III is synthesized under the action of an acid-binding agent, and then the condensation reagent III reacts with voriconazole to obtain a key intermediate II of voriconazole phosphocholine inner salt, wherein the reaction formula is as follows:
8. the preparation method of key intermediate of voriconazole phosphocholine ester inner salt according to claim 7, wherein the acid-binding agent is organic base or inorganic base.
9. The preparation method of the tazobactam key intermediate as claimed in claim 7, wherein in the process of obtaining the condensation reagent III from choline chloride, the reaction temperature is controlled to be-10 ℃ to 40 ℃, the reaction time is 1 to 12 hours, and the reaction solvent is: dichloromethane, ethyl acetate, isopropyl acetate, methyl tert-ether or toluene.
10. The preparation method of the key intermediate of voriconazole phosphocholine inner salt according to claim 7, characterized in that, in the process of obtaining the key intermediate II of voriconazole phosphocholine inner salt by the condensation reagent III, the reaction is carried out under the action of 1H-tetrazole, the reaction temperature is controlled to be-10 ℃ to 70 ℃, the reaction time is 1 to 16 hours, and the reaction solvent is: dichloromethane, acetonitrile, ethyl acetate, isopropyl acetate, methyl tert-ether or toluene.
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| CN102439018A (en) * | 2009-03-19 | 2012-05-02 | 塞普斯制药有限公司 | Fosfluconazole derivatives, synthesis, and use in long acting formulations |
| US20150071861A1 (en) * | 2012-05-23 | 2015-03-12 | Canon Kabushiki Kaisha | Polymer, contrast agent for nuclear magnetic resonance analysis or magnetic resonance imaging using the polymer, compound and method of nuclear magnetic resonance analysis and method of magnetic resonance imaging using the polymer |
| CN106432339A (en) * | 2015-08-08 | 2017-02-22 | 陕西合成药业股份有限公司 | Voriconazole derivative, synthesis thereof, and use thereof in long-acting preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102439018A (en) * | 2009-03-19 | 2012-05-02 | 塞普斯制药有限公司 | Fosfluconazole derivatives, synthesis, and use in long acting formulations |
| US20150071861A1 (en) * | 2012-05-23 | 2015-03-12 | Canon Kabushiki Kaisha | Polymer, contrast agent for nuclear magnetic resonance analysis or magnetic resonance imaging using the polymer, compound and method of nuclear magnetic resonance analysis and method of magnetic resonance imaging using the polymer |
| CN106432339A (en) * | 2015-08-08 | 2017-02-22 | 陕西合成药业股份有限公司 | Voriconazole derivative, synthesis thereof, and use thereof in long-acting preparation |
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