CN106397417A - Preparation method for preparing posaconazole midbody - Google Patents
Preparation method for preparing posaconazole midbody Download PDFInfo
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- CN106397417A CN106397417A CN201610771038.8A CN201610771038A CN106397417A CN 106397417 A CN106397417 A CN 106397417A CN 201610771038 A CN201610771038 A CN 201610771038A CN 106397417 A CN106397417 A CN 106397417A
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- dichloromethane
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- RAGOYPUPXAKGKH-XAKZXMRKSA-N posaconazole Chemical compound O=C1N([C@H]([C@H](C)O)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3C[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 RAGOYPUPXAKGKH-XAKZXMRKSA-N 0.000 title claims abstract description 14
- 229960001589 posaconazole Drugs 0.000 title claims abstract description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 33
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229940125782 compound 2 Drugs 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 229940126214 compound 3 Drugs 0.000 claims abstract description 8
- 229940125898 compound 5 Drugs 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 5
- 150000003852 triazoles Chemical class 0.000 claims abstract description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 95
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 19
- 239000000376 reactant Substances 0.000 claims description 18
- 239000007787 solid Substances 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- 239000003921 oil Substances 0.000 claims description 17
- 208000035126 Facies Diseases 0.000 claims description 14
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 14
- -1 p-toluenesulfonyl Chemical group 0.000 claims description 14
- 229940125904 compound 1 Drugs 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 9
- 238000000746 purification Methods 0.000 claims description 9
- 238000010898 silica gel chromatography Methods 0.000 claims description 9
- 238000000605 extraction Methods 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 7
- GUVUOGQBMYCBQP-UHFFFAOYSA-N dmpu Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- 229910052710 silicon Inorganic materials 0.000 claims description 2
- 239000010703 silicon Substances 0.000 claims description 2
- FDNAPBUWERUEDA-UHFFFAOYSA-N silicon tetrachloride Chemical compound Cl[Si](Cl)(Cl)Cl FDNAPBUWERUEDA-UHFFFAOYSA-N 0.000 claims description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 2
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 claims 3
- SHAHPWSYJFYMRX-GDLCADMTSA-N (2S)-2-(4-{[(1R,2S)-2-hydroxycyclopentyl]methyl}phenyl)propanoic acid Chemical compound C1=CC([C@@H](C(O)=O)C)=CC=C1C[C@@H]1[C@@H](O)CCC1 SHAHPWSYJFYMRX-GDLCADMTSA-N 0.000 claims 2
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 claims 2
- 238000004440 column chromatography Methods 0.000 claims 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 101000905241 Mus musculus Heart- and neural crest derivatives-expressed protein 1 Proteins 0.000 claims 1
- TZYWCYJVHRLUCT-VABKMULXSA-N N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal Chemical compound CC(C)C[C@@H](C=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCC1=CC=CC=C1 TZYWCYJVHRLUCT-VABKMULXSA-N 0.000 claims 1
- 150000001335 aliphatic alkanes Chemical class 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 230000001934 delay Effects 0.000 claims 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 claims 1
- 239000012535 impurity Substances 0.000 abstract description 4
- 238000007086 side reaction Methods 0.000 abstract description 2
- 230000007547 defect Effects 0.000 abstract 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical class [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 abstract 1
- 230000000694 effects Effects 0.000 abstract 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 abstract 1
- 229910000077 silane Inorganic materials 0.000 abstract 1
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 239000007832 Na2SO4 Substances 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 0 OC[C@@]1C[C@](CC(C=C=CC(F)=C2)=C2F)(CI)*C1 Chemical compound OC[C@@]1C[C@](CC(C=C=CC(F)=C2)=C2F)(CI)*C1 0.000 description 4
- 239000003208 petroleum Substances 0.000 description 3
- 238000010791 quenching Methods 0.000 description 3
- 230000000171 quenching effect Effects 0.000 description 3
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 229940121375 antifungal agent Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 230000000269 nucleophilic effect Effects 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- LVTWOZLZNXOFBU-SSDOTTSWSA-N CC(OC[C@H]1COCC1)=O Chemical compound CC(OC[C@H]1COCC1)=O LVTWOZLZNXOFBU-SSDOTTSWSA-N 0.000 description 1
- ONKOIEIAYFRQMU-UHFFFAOYSA-N C[F]c(cc1)cc(F)c1I Chemical compound C[F]c(cc1)cc(F)c1I ONKOIEIAYFRQMU-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000032826 Ring chromosome 3 syndrome 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
- MOFINMJRLYEONQ-UHFFFAOYSA-N [N].C=1C=CNC=1 Chemical class [N].C=1C=CNC=1 MOFINMJRLYEONQ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 239000003429 antifungal agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000010322 bone marrow transplantation Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- 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
- C07B2200/07—Optical isomers
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a method for preparing a posaconazole midbody shown as the formula 1. According to the preparation method, a compound 2 reported in literature is used as a raw material; firstly, trialkyl silane is used for protecting hydroxyl to obtain a compound 3; then, the compound 3 takes a reaction with sodium salts 4 of triazole to obtain a compound 5; next, siloxane removal is performed under the effects of paratoluensulfonyl chloride and alkali, and toluenesulfonyl protection is performed to obtain a compound 1. The method provided by the invention can overcome the defects in the prior art; a splicing step is not performed; the occurrence of side reaction and the appearance of impurities are reduced; the reaction selectivity and the yield are improved. The formulas are shown as the accompanying drawing.
Description
Technical field
The present invention relates to a kind of preparation method of organic compound, it is Specifically that its structure is as shown in Equation 1 can use
Preparation method in the compound 1 preparing antifungal agent posaconazole (Posaconazo le) intermediate.
Background technology
Posaconazole (Posaconazo le), the antifungal developed for celestial spirit-Schering-Plough (Schering-Plough)
New drug.Be mainly used in those because after bone marrow transplantation immunity weaken with numeration of leukocyte reduce patient, to prevent some mycetes
The infection causing with yeast-like fungi.The body of these patients is difficult to resist above-mentioned infection after accepting cancer chemotherapy.U.S. FDA
In September in 2006 approval on the 18th.
The English language Chemical title of posaconazole is：4-[4-[4-[4-[[(3R,5R)-5-(2,4-Difluorophenyl)-
5-(1,2,4-triazol-1-ylmethyl)oxolan-3-yl]methoxy]phenyl]piperazin-1-yl]
phenyl]-2-[(2S,3S)-2-hydroxypentan-3-yl]-1,2,4-triazol-3-one；Chinese chemical name：4-
[4- [4- [4- [[(3R, 5R) -5- (2,4 difluorobenzene base) -5- (1,2,4- triazol-1-yl methyl) oxa- penta ring -3- base] methoxy
Base] phenyl] piperazine -1- base] phenyl] -2- [the amyl- 3- yl of (2S, 3S) -2- hydroxyl] -1,2,4- triazole -3- ketone；Molecular formula：
C37H42F2N8O4；Relative molecular weight：700.78；CAS registration number：171228-49-2.Posaconazole since the advent of the world, domestic
There is outward a lot of patents and document report its preparation method.
Patent WO2013042138A2 reports following route synthesising target compound：But the presence of hydroxyl leads to three
When nitrogen azoles connects, it is susceptible to intramolecular nucleophilic channel (hydroxyl replacement iodine), yield is low, and impurity is obvious.
US5403937A reports following route and has synthesized target compound：The same with above-mentioned route, hydroxyl leads to
Reaction selectivity is poor, and inner molecular reaction can react generation impurity between disturbing molecule, reduces yield.
WO9517407A1, US5661151A, WO9638443A1 report following synthetic route：This route synthesis condition
Complexity, and building-up process will be through splitting, and the yield of resolution reaction is less than 40%, and combined coefficient is extremely low.
Content of the invention
For the problem overcoming above-mentioned route to exist, the present invention provides a kind of preparation being greatly improved compound 1 to receive
The preparation method of rate.
The preparation method is that with document it has been reported that compound 2 be raw material, protected with trialkyl silyl first
Hydroxyl obtains compound 3, then reacts with the sodium salt 4 of triazole again, obtains compound 5, then in paratoluensulfonyl chloride and alkali
In the presence of desiliconization ether carry out p-toluenesulfonyl protection and obtain compound 1, the trialkyl silyl in preparation method of the present invention,
I.e. R can be trimethyl silicane or triethyl group silicon or t-Butyldimethylsilyl, and alkali used is potassium carbonate or sodium carbonate
Or sodium bicarbonate or triethylamine or pyridine or imidazoles.
Avoid in preparation process of the present invention that (intramolecular nucleophilic takes with the disturbing reaction of hydroxyl during triazole coupling reaction
Generation reaction), without splitting step, occur with decreasing side reaction generation and impurity, improve selectivity and the yield of reaction.
Specific embodiment
It is in DMF or dichloromethane that compound 2 is dissolved in DMF, is then added thereto to suitably
Alkali, and trialkyl silicon chloride RX.Obtain compound 3 after the completion of reaction, directly its DMF solution is carried out next step or enter
Row be quenched, extract, being dried, concentrate post processing after be re-dissolved in DMF carrying out next step reaction.
Above-mentioned gained compound 3 is dissolved in DMF, in reactant liquor, then adds 3-5 times of mole
Triazole sodium salt compound 4 and the DMPU of 1-1.5 mole, are heated to 80-140 DEG C and stir 24 hours, after the completion of reaction, add water
Reaction is quenched, with dichloromethane extraction, gained organic faciess are the solution of compound 5, can by silica gel column chromatography purification or
Purified with such a way：With saturated common salt water washing organic faciess, then use salt acid extraction, gained aqueous hydrochloric acid solution is water-soluble with KOH
Liquid or NaOH aqueous solution or sodium bicarbonate aqueous solution or aqueous sodium carbonate tune PH=8-9, are then extracted with ethyl acetate
Take, then be dried, concentrate after obtain yellow oil, then with ethyl acetate and normal hexane crystallization obtain faint yellow solid 5.
The compound 5 obtaining is added in dichloromethane, adds 1-1.5 to be rubbed by the triethylamine of mole and 0.01-0.1
The DMAP of your amount, is then dividedly in some parts the paratoluensulfonyl chloride of 1-1.5 mole, reaction is stirred at room temperature at 0 DEG C
After the completion of, through extraction, acid-alkali washing, drying, filter, be evaporated after obtain yellow oil, purified with silica gel column chromatography or
Obtain the high white solid of purity 1 with isopropanol and petroleum ether crystallization.
Embodiment one：
1mmol compound 2 is dissolved in DMF, is then added thereto to 1.1mmol potassium carbonate, stirs
Mix down that to be slowly added dropwise thereto into 1.2mmol trim,ethylchlorosilane be TMSCl.After 1h, that is, obtain the solution of 3a, then to reaction
In liquid, addition 4mmol triazole sodium salt compound 4 and 1.2mmol 1,3- dimethyl -3,4,5,6- tetrahydrochysene -2 (1H) pyrimidone are
DMPU, is heated to 100-110 DEG C and stirs 24 hours, TLC shows and completes.Add water (1.5L), is extracted with dichloromethane (50ml*2),
Dichloromethane saturated aqueous common salt (20mL) washed once, then is extracted with 15%HCl (40ml*2), aqueous hydrochloric acid solution dichloromethane
Alkane (40ml*2) washs, and aqueous hydrochloric acid solution adjusts PH=8-9 with 50%NaOH (about 100mL), is extracted with ethyl acetate (70ml*2),
Saturated aqueous common salt (500ml*2) washs, Na2SO4It is dried, concentrates, obtain yellow oil, add ethyl acetate (100ml), stir
Mix 10min), it is dividedly in some parts normal hexane (common 20ml), 0 DEG C of stirring 2h, sucking filtration, obtain faint yellow solid 5a, yield 56.6% is pure
Degree 90%.
Take 0.8mmol 5a to be added in dichloromethane, add 1mmol pyridine, 0.1mmol DMAP is
DMAP.0 DEG C is dividedly in some parts 1mmol paratoluensulfonyl chloride is TsCl, is stirred at room temperature 1 day, reaction completes.Reactant liquor is poured into
In 1mol/L aqueous hydrochloric acid solution (20ml), add dichloromethane (20ml), point liquid, organic faciess are washed with 1mol/L hydrochloric acid (20ml)
Wash, then use saturation Na2CO3(500ml*2) wash, Na2SO4It is dried, filter, be spin-dried for, obtain yellow oil, plus isopropanol
(5ml), stir 5min, be dividedly in some parts petroleum ether (30ml), stir 2 hours, filter, petroleum ether (20ml) washs, and dries and obtains
White solid 1, with isopropanol 30ml in 60 DEG C of recrystallization, obtain the high white solid of purity 1, yield 48%, purity
98.5%.
Embodiment two：
3mmol compound 2 is dissolved in dichloromethane 20mL, is then added thereto to 3.3mmol imidazoles, under stirring to
Wherein being slowly added dropwise into 3.6mmol chlorotriethyl silane is TESCl.After 1h, add water quenching to go out in reactant liquor, then divide liquid,
All organic faciess are concentrated to dryness after being dried and obtain 3b.
2mmol 3b is dissolved in 10mLDMF, adds 10mmol triazole sodium salt compound 4 He in reactant liquor
2mmol1,3- dimethyl -3,4,5,6- tetrahydrochysene -2 (1H) pyrimidones are DMPU, are heated to 100-110 DEG C and stir 24 hours.Add water
(1.5L) it is quenched, is extracted with dichloromethane (50ml*2), dichloromethane saturated aqueous common salt (20mL) washed once, Na2SO4
It is dried, concentrate, obtain yellow oil, silica gel column chromatography purification obtains faint yellow solid 5b, yield 46%, purity 96%.
Take 0.8mmol 5a to be added in dichloromethane, add 1mmol triethylamine, 0.05mmol DMAP.
0 DEG C is dividedly in some parts 1mmol paratoluensulfonyl chloride, is stirred at room temperature 1 day, reaction completes.Reactant liquor is poured into 1mol/L hydrochloric acid water-soluble
In liquid (20ml), add dichloromethane (20ml), point liquid, organic faciess are washed with 1mol/L hydrochloric acid (20ml), then use saturation Na2CO3
(500ml*2) wash, Na2SO4It is dried, filters, be spin-dried for, obtain yellow oil, silica gel column chromatography purification obtains high white of purity
Color solid 1, yield 54%, purity 98.0%
Embodiment three：
3mmol compound 2 is dissolved in DMF, is then added thereto to 3.3mmol pyridine, stirring
Under to be slowly added dropwise thereto into 3.6mmol tert-butyl chloro-silicane be TBDMSCl.After 1h, add water quenching in reactant liquor
Go out, then divide liquid, all organic faciess are concentrated to dryness after being dried and obtain 3b.
2mmol 3b is dissolved in 10mLDMF, adds 10mmol triazole sodium salt compound 4 and 2mmol in reactant liquor
DMPU, is heated to 100-110 DEG C and stirs 24 hours.Add water (1.5L) be quenched, with dichloromethane (50ml*2) extraction, dichloromethane
Mutually be washed once with saturated aqueous common salt (20mL), Na2SO4It is dried, concentrate, obtain yellow oil, silica gel column chromatography purification obtains
Faint yellow solid 5b, yield 51%, purity 96%.
Take 0.8mmol 5a to be added in dichloromethane, add 1mmol potassium carbonate, 0.03mmol DMAP.
0 DEG C is dividedly in some parts 1mmol paratoluensulfonyl chloride, is stirred at room temperature 1 day, reaction completes.Reactant liquor is poured into 1mol/L hydrochloric acid water-soluble
In liquid (20ml), add dichloromethane (20ml), point liquid, organic faciess are washed with 1mol/L hydrochloric acid (20ml), then use saturation Na2CO3
(500ml*2) wash, Na2SO4It is dried, filters, be spin-dried for, obtain yellow oil, silica gel column chromatography purification obtains high white of purity
Color solid 1, yield 50%, purity 99.5%
Example IV：
Compound 354g 2 is dissolved in 4L dichloromethane, is then added thereto to 120g triethylamine, to it under stirring
In to be slowly added dropwise into 165g chlorotriethyl silane be TESCl.After 1h, add water quenching to go out in reactant liquor, then divide liquid, Suo Youyou
Machine phase is concentrated to dryness after being dried and obtains 3b.
375g 3b is dissolved in 600mLDMF, adds 270g triazole sodium salt compound 4 and 1,3- diformazan in reactant liquor
Base -3,4,5,6- tetrahydrochysene -2 (1H) pyrimidones are DMPU, are heated to 100-110 DEG C and stir 24 hours.Add water (1.5L) be quenched, use
Dichloromethane (1000ml*2) extracts, and dichloromethane saturated aqueous common salt (200mL) washed once, Na2SO4It is dried, concentrate,
Obtain yellow oil, silica gel column chromatography purification obtains faint yellow solid 5b, yield 55%, purity 97%.
Take 210g 5a to be added in 1500mL dichloromethane, add 60g triethylamine, 1.2g DMAP.0℃
It is dividedly in some parts 120g paratoluensulfonyl chloride, be stirred at room temperature 1 day, reaction completes.Reactant liquor is poured in 1mol/L aqueous hydrochloric acid solution
(2000ml), add dichloromethane (1000ml), point liquid, organic faciess are washed with 1mol/L hydrochloric acid (1000ml), then use saturation
Na2CO3(500ml*2) wash, Na2SO4It is dried, filter, be spin-dried for, obtain yellow oil, silica gel column chromatography purification obtains purity
High white solid 1, yield 53%, purity 98.8%.
Claims (5)
1. the preparation method of the compound 1 of the intermediate preparing posaconazole showing as formula 1 it is characterised in that as formula 5 is shown, with changing
Compound 2 is raw material, obtains compound 3 with trialkyl silyl protection hydroxyl first, then reacts with the sodium salt 4 of triazole again, obtain
To compound 5, then desiliconization ether carry out p-toluenesulfonyl protection and obtain chemical combination in the presence of paratoluensulfonyl chloride and alkali
Thing 1,
In reaction equation, R can be trimethyl silicane or triethyl group silicon or t-Butyldimethylsilyl, and alkali used is potassium carbonate
Or sodium carbonate or sodium bicarbonate or triethylamine or pyridine or imidazoles.
2. the preparation method of the compound 1 of the intermediate preparing posaconazole showing as formula 1 according to claim 1, its
It is characterised by that preparing formula 6 such as shows, that is,：It is DMF or dichloromethane that compound 2 is dissolved in N,N-dimethylformamide
In alkane, then it is added thereto to alkali and trialkyl silicon chloride RX, reaction obtains compound 3, compound 3 is dissolved in N, N- bis-
In methylformamide, in reactant liquor, then add the triazole sodium salt compound 4 of 3-5 times of mole and 1-1.5 mole
DMPU, is heated to 80-140 DEG C and is reacted, and is quenched and reacts molten for compound 5 through organic faciess are obtained by extraction after the completion of reaction
Liquid, purified after obtain the compound 5 of faint yellow solid, compound 5 is added in dichloromethane, adds triethylamine and 4- bis-
Methylamino pyridine, is then dividedly in some parts the paratoluensulfonyl chloride of 1-1.5 mole at 0 DEG C, and reaction is stirred at room temperature, and reaction completes
Afterwards, obtain yellow oil after extraction, acid-alkali washing, drying, filtration, dried, then after column chromatography or recrystallization
Obtain the compound 1 of white solid.
3. the preparation method of the compound 1 of the intermediate preparing posaconazole showing as formula 1 according to claim 1, its
It is characterised by：Compound 2 is dissolved in dichloromethane, is then added thereto to imidazoles, be slowly added dropwise thereto under stirring into
Chlorotriethyl silane is reacted, and reaction is then quenched, and the organic faciess obtaining after point liquid obtain chemical combination after drying concentrates again
Thing 3b, compound 3b is dissolved in DMF, addition triazole sodium salt compound 4 and 1,3- dimethyl -3 in reactant liquor, and 4,5,6-
Tetrahydrochysene -2 (1H) pyrimidone, is heated to 100-110 DEG C of reaction, reaction is then quenched, and through extraction, washing, is dried and concentration
Obtain yellow oil, then obtain faint yellow solid 5b through column chromatography purification, 5a is added in dichloromethane, add three second
Amine and DMAP, 0 DEG C is dividedly in some parts paratoluensulfonyl chloride, pours reactant liquor into aqueous hydrochloric acid solution after the completion of reaction
In, add dichloromethane, organic faciess are washed, are dried, filtering after processing by point liquid, be spin-dried for process after obtain yellow oil,
Purified process obtains target compound 1 again.
4. the preparation method of the compound 1 of the intermediate preparing posaconazole showing as formula 1 according to claim 1, its
It is characterised by：Compound 2 is dissolved in DMF, is then added thereto to pyridine, delays thereto under stirring
Slowly it is added dropwise to tert-butyl chloro-silicane, reaction after reaction, is quenched, then divide liquid, organic faciess are concentrated to give compound after being dried
3b, compound 3b is dissolved in DMF, adds triazole sodium salt compound 4 and DMPU, be heated to 100-110 DEG C in reactant liquor
It is quenched after stirring reaction, through extraction, washing, be dried and obtain yellow oil after concentrating, more purified obtain faint yellow solid
5b, compound 5a is added in dichloromethane, adds potassium carbonate, DMAP, 0 DEG C is dividedly in some parts tolysulfonyl
Chlorine, is stirred at room temperature reaction, after the completion of reaction pours reactant liquor in aqueous hydrochloric acid solution into, adds dichloromethane, then divides liquid, has
Machine is mutually scrubbed, dry, be filtrated to get yellow oil, and silica gel column chromatography purification obtains the compound 1 of white solid.
5. the preparation method of the compound 1 of the intermediate preparing posaconazole showing as formula 1 according to claim 1, its
It is characterised by：Compound 2 is dissolved in dichloromethane, then thereto plus triethylamine, be slowly added dropwise thereto under stirring into
Chlorotriethyl silane, is quenched reaction after fully reacting, and point liquid is processed, organic faciess are concentrated to give compound 3b, by chemical combination after being dried
Thing 3b is dissolved in DMF, adds triazole sodium salt compound 4 and 1,3- dimethyl -3,4,5,6- tetrahydrochysenes -2 (1H) in reactant liquor
Pyrimidone, is quenched after being heated to 100-110 DEG C of stirring reaction, through extracting, washed once, be dried and concentration obtain yellow oil
Shape thing, the more purified compound 5b obtaining faint yellow solid, compound 5a are added in dichloromethane, add triethylamine
And DMAP, 0 DEG C is dividedly in some parts paratoluensulfonyl chloride, and room temperature pours reactant liquor into hydrochloric acid water after the completion of fully reacting
In solution, add dichloromethane, organic faciess washing after point liquid, be dried, filter after obtain yellow oil, more purified obtain
The compound 1 of white solid.
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|---|---|---|---|---|
| CN114920686A (en) * | 2022-05-20 | 2022-08-19 | 山东农业大学 | Synthesis method of 5- (benzenesulfonyl) -N-piperidin-4-yl-2- (trifluoromethyl) benzenesulfonamide hydrochloride |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1073944A (en) * | 1991-10-30 | 1993-07-07 | 先灵公司 | Tri-substituted tetrahydrofuran antifungals |
| WO2009141837A2 (en) * | 2008-05-21 | 2009-11-26 | Ind-Swift Laboratories Limited | Process for preparing posaconazole and intermediates thereof |
| CN102892763A (en) * | 2010-05-19 | 2013-01-23 | 桑多斯股份公司 | Purification of posaconazole and posaconazole intermediates |
| CN102906087A (en) * | 2010-05-19 | 2013-01-30 | 桑多斯股份公司 | Method for preparing chiral triazolones |
| WO2015059716A2 (en) * | 2013-10-22 | 2015-04-30 | Msn Laboratories Private Limited | Improved process for the preparation of ((3s,5r)-5-((1h-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate |
| CN105440022A (en) * | 2015-12-31 | 2016-03-30 | 重庆威鹏药业有限公司 | Preparation method of posaconazole main ring |
-
2016
- 2016-08-30 CN CN201610771038.8A patent/CN106397417A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1073944A (en) * | 1991-10-30 | 1993-07-07 | 先灵公司 | Tri-substituted tetrahydrofuran antifungals |
| WO2009141837A2 (en) * | 2008-05-21 | 2009-11-26 | Ind-Swift Laboratories Limited | Process for preparing posaconazole and intermediates thereof |
| CN102892763A (en) * | 2010-05-19 | 2013-01-23 | 桑多斯股份公司 | Purification of posaconazole and posaconazole intermediates |
| CN102906087A (en) * | 2010-05-19 | 2013-01-30 | 桑多斯股份公司 | Method for preparing chiral triazolones |
| WO2015059716A2 (en) * | 2013-10-22 | 2015-04-30 | Msn Laboratories Private Limited | Improved process for the preparation of ((3s,5r)-5-((1h-1,2,4-triazol-1-yl)methyl)-5-(2,4-difluorophenyl)tetrahydrofuran-3-yl)methyl-4-methylbenzenesulfonate |
| CN105440022A (en) * | 2015-12-31 | 2016-03-30 | 重庆威鹏药业有限公司 | Preparation method of posaconazole main ring |
Non-Patent Citations (3)
| Title |
|---|
| LEMENEZ， P ET AL.: "Sequential Homoaldolization - Cuprate Rearrangement In A Stereoselective Synthesis Of Stannyl Dienes - Application To The Synthesis Of The Western C10-C15 Subunit Of ±-Tylosin Aglycon", 《JOURNAL OF ORGANIC CHEMISTRY》 * |
| YODA，H，ET AL.: "Diastereoselective Reactions Of Grignard-Reagents With Chiral Amino Lactols Derived From L-Aspartic Acid", 《TETRAHEDRON-ASYMMETRY》 * |
| 黄培强等: "《有机合成》", 30 June 2004, 高等教育出版社 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114920686A (en) * | 2022-05-20 | 2022-08-19 | 山东农业大学 | Synthesis method of 5- (benzenesulfonyl) -N-piperidin-4-yl-2- (trifluoromethyl) benzenesulfonamide hydrochloride |
| CN114920686B (en) * | 2022-05-20 | 2023-11-24 | 山东农业大学 | Synthesis method of 5-(phenylsulfonyl)-N-piperidin-4-yl-2-(trifluoromethyl)benzenesulfonamide hydrochloride |
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