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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- 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
- 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
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- 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
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- 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
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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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Cited By (1)
| 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 |
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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- (benzenesulfonyl) -N-piperidin-4-yl-2- (trifluoromethyl) benzenesulfonamide hydrochloride |
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Application publication date: 20170215 |