CN108059624A - It is used to prepare the preparation method of click azoles amine key intermediate - Google Patents
It is used to prepare the preparation method of click azoles amine key intermediate Download PDFInfo
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- CN108059624A CN108059624A CN201610980569.8A CN201610980569A CN108059624A CN 108059624 A CN108059624 A CN 108059624A CN 201610980569 A CN201610980569 A CN 201610980569A CN 108059624 A CN108059624 A CN 108059624A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D263/18—Oxygen atoms
- C07D263/20—Oxygen atoms attached in position 2
- C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
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- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Abstract
The invention discloses a kind of preparation methods for being used to prepare click azoles amine key intermediate, include the following steps：Formula (4) compound and non-nucleophilic highly basic are acted on, then reacted with (R) Glycidyl butyrate, reaction solution adds in the reactant aqueous solution of nucleopilic reagent solution and acid at room temperature, then from reaction product, collects described formula (1) compound；The present invention replaces aqueous ammonium chloride solution with the aqueous solution of nucleopilic reagent solution and acid, reduces impurity a and b generation, and yield is improved by 65.5% to 78.5%~88.5%.Reaction expression is as follows：
Description
Technical field
The present invention relates to a kind of preparation methods of click azoles amine key intermediate, and in particular to compound (5R) -3- (4- benzyls
Oxygroup -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1) preparation method.
Background technology
Click azoles amine (cadazolid) is developed by Actelion companies of Switzerland, is a kind of mosaic type antibacterials, Ju You Evil
Oxazolidone and fluoquinolone structure for treating clostridium difficile associated diarrhea, are currently in III phase clinical investigation phase.
(5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1) is the key that prepare click azoles amine
Intermediate, structural formula are as follows：
At present, the preparation method of the published intermediate is as follows both at home and abroad：
(1) WO2005/058888 disclose one kind (5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidines -
The preparation method of 2- ketone (1)：
It concretely comprises the following steps：The fluoro- 4- nitrobenzenes (2) of 1- benzyloxies -2- through platinum charcoal catalytic hydrogen reduction, acylation, in normal-butyl
The lower cyclization of lithium effect obtains formula (1) compound.Route nitro reduction is using expensive platinum carbon catalyst, and the reaction time is long, reference
Literature procedures, 48h still can not the reaction was complete；Ring closure reaction temperature requirement is harsh, needs to react at -78 DEG C, equipment requirement is high, yield
Only 65.5%.
(2) WO2016/079757 disclose one kind (5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidines -
The preparation method of 2- ketone (1)：
It concretely comprises the following steps：Formula (2) compound is through platinum charcoal catalytic hydrogen reduction, nucleophilic addition, aminoacylates, condensation cyclization etc.
Formula (1) compound is obtained by the reaction.The route steps are more, and purification of intermediate is difficult, and nitro reduction need to use expensive platinum charcoal to be catalyzed
Agent, the reaction time is long, and hydrogenation equipment requirement is high, is unfavorable for amplification production.
To sum up, formula (1) compound is to prepare an important intermediate of click azoles amine, it has been disclosed that technical method has examination
Agent costliness, the shortcomings such as intermediate purity difference, equipment requirement are high, yield is low, it is difficult to carry out industrial amplification production.Therefore, develop
The variation route for being suitble to industrialized production is very necessary.
The content of the invention
It is existing to overcome it is an object of the invention to disclose a kind of preparation method for being used to prepare click azoles amine key intermediate
There is drawbacks described above existing for technology.
Described to be used to prepare click azoles amine key intermediate, chemical name is (5R) -3- (4- benzyloxy -3- fluorobenzene
Base) -5- Qiang Jia Ji oxazolidine -2- ketone, structural formula is as follows：
Preparation method includes the following steps：
Formula (4) compound and non-nucleophilic highly basic are acted on, then reacted under low temperature with (R)-Glycidyl butyrate
0.25h~1.5h, more preferable 0.25~0.5h, reaction solution add in the aqueous solution of nucleopilic reagent solution and acid, reaction at room temperature
0.25~2h removes byproduct of reaction, then from reaction product, collection type (1) compound；
Reaction expression is as follows：
The preferred potassium hexamethyldisilazide of the non-nucleophilic highly basic, sodium hexamethyldisilazide, two silicon of hexamethyl
Base amido lithium or lithium diisopropylamine, more preferable hexamethyldisilazide lithium；
Preferably -10~10 DEG C, more preferably -5~5 DEG C of the low temperature；
The nucleopilic reagent is selected from C1~C5Saturated fat alkoxide, preferably potassium tert-butoxide, sodium tert-butoxide, tert-butyl alcohol lithium, methanol
Sodium, sodium ethoxide, potassium methoxide, potassium ethoxide, more preferable sodium methoxide；
The preferred C of acid1~C4Aliphatic acid, tartaric acid, maleic acid, malonic acid, ethanedioic acid, adipic acid, sulfuric acid, hydrochloric acid,
More preferable hydrochloric acid；
The nucleopilic reagent and the molar ratio preferably 1 of formula (4) compound:3~1:6, more preferable 1:4~1:4.5；The parent
The mass fraction of core reagent solution, preferably 20%-30%；
The nucleopilic reagent solution is the organic solvent containing the nucleopilic reagent, and the organic solvent is selected from first
Alcohol, ethyl alcohol or the tert-butyl alcohol；
The acid and the molar ratio preferably 1 of formula (4) compound:1.05~1:2.The concentration of aqueous solution preferably 2 of the acid~
12mol/L, more preferable 3~6mol/L；
It tests and finds with reference to WO2005/058888, this reaction generates substantial amounts of ester by-products (a) and crosses alkylation by-product
Object (b), a and b contents respectively may be about 24% and 13% in crude product, and structure is as follows：
And the method for the present invention, the content of by-product a and b in crude product are down to 0.01% and 3% respectively；
The collection method, preferably recrystallizes, the preferred methanol of recrystallization solvent, ethyl alcohol, isopropanol, ethyl acetate, oil
Ether, n-hexane and normal heptane knot or its mixture, more preferable isopropanol；
It is prepared by the method that WO2005/058888 document reports can be used in formula (4) compound；
The novelty of the present invention is embodied in：Formula (4) compound is shunk sweet under the effect of non-nucleophilic highly basic with (R)-butyric acid
Grease reacts cyclization, sequentially adds the aqueous solution of nucleopilic reagent solution and acid, obtains formula (1) compound.
The beneficial effects of the invention are as follows：
With nucleopilic reagent solution and acid aqueous solution replace aqueous ammonium chloride solution, reduce impurity a and b generate, yield by
65.5% improves to 78.5%~88.5%.
To sum up, the present invention shortens without expensive reducing agent, reaction time, and feed stock conversion improves.Reaction condition is mild, behaviour
Make simplicity, it is at low cost, possess the potentiality of industrialized production.
Specific implementation method
It is further illustrated the present invention below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a scope.
In embodiment, formula (4) compound is prepared or commercially available using the method for WO2005/058888 document reports
It obtains.
Embodiment 1 (5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1)
Formula (4) compound (90g, 0.256mol) is added in 900ml anhydrous tetrahydro furans.Two silicon of 1.0M hexamethyls is added dropwise
Base lithium amide hexane solution (267ml, 0.269mol), is stirred at room temperature 1h, is cooled to 0 DEG C, adds in R- (-)-glycidol butyric acid
Ester (38.7g, 0.269mol) stirs 0.5h, is warmed to room temperature.Add in the methanol solution (32ml) of 30% sodium methoxide, stirring
15min adds 6M hydrochloric acid 43ml.Reaction solution is concentrated under reduced pressure, and obtains white slurry, adds in water (450ml) and dilutes, and filtering obtains
To crude white solid (HPLC contents：Impurity a 0.01%, impurity b 3%).It is white that crude product with recrystallisation from isopropanol obtains 71.82g
Color solid 1, as described (5R) -3- (4- benzyloxy -3- the fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1), yield
88.5%.
ESI-MS(m/z):318[M+H]+；
1H NMR(400MHz,CDCl3)δ:7.53-7.29 (m, 6), 7.13-7.04 (m, 1H), 6.97 (t, J=9.0Hz,
1H), 5.12 (s, 2), 4.72 (ddd, J=12.6,7.0,3.7Hz, 1H), 4.13-3.85 (m, 3), 3.86-3.63 (m, 1H),
2.30(s,1H).
Embodiment 2 (5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1)
It is operated with reference to WO2005/058888
Formula (4) compound (50g, 0.142mol) is added in 500ml anhydrous tetrahydro furans.2.5M n-BuLis are added dropwise
1h is stirred at room temperature in (6.0ml, 0.149mol), is cooled to -78 DEG C, add in R- (-)-Glycidyl Butyrate (24.6g,
0.171mol).After stirring 0.5h, it is warmed to room temperature.The methanol solution 32ml stirring 15min of 30% sodium methoxide sodium are added in, then are added
Enter 6M hydrochloric acid solutions 28ml.Reaction solution vacuum rotary steam, adds in water (250ml, 5 volumes), and filtering obtains faint yellow solid crude product
(HPLC contents：Impurity a 24%, impurity b 13%).Crude product obtains 25.9g white solids 1 with recrystallisation from isopropanol, is described
(5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1), yield 57.5%.
Embodiment 3 (5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1)
Formula (4) compound (50g, 0.142mol) is added in 500ml anhydrous tetrahydro furans.2.0M diisopropyl ammonia is added dropwise
1h is stirred at room temperature in base lithium (75ml, 0.149mol), is cooled to -5 DEG C, add in R- (-)-Glycidyl Butyrate (21.54g,
0.149mol).Stir 0.5 it is small when after, be warmed to room temperature.The ethanol solution 18ml stirring 15min of 20% sodium ethoxide are added in, then are added
Enter the acetic acid aqueous solution 28ml of 5M.Reaction solution vacuum rotary steam, adds in water (250ml, 5 volumes), and filtering obtains crude white solid
(HPLC contents：Impurity a0.11%, impurity b8%).Crude product obtains 35.1g white solids 1 with recrystallisation from isopropanol, is described
(5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1), yield 78.5%.
Embodiment 4 (5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1)
Formula (4) compound (20g, 0.057mol) is added in 200m anhydrous tetrahydro furans.Two silicon of 1.0M hexamethyls is added dropwise
Base Sodamide (59ml, 0.059mol) cools down less than -5 DEG C, adds in R- (-)-Glycidyl Butyrate (8.6g, 0.059mol).
It is warmed to room temperature after stirring 1.5h, adds in the t-butanol solution 15.9ml stirring 15min of 20% potassium tert-butoxide, add the sulphur of 3M
Aqueous acid 19.9ml.By reaction solution vacuum rotary steam, water (100ml, 5 volumes) is added in, filtering obtains crude white solid
(HPLC contents：Impurity a0.22%, impurity b12%).Crude product obtains 14.76g white solids 1 with recrystallisation from isopropanol, is described
(5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1), yield 82%.
Embodiment 5 (5R) -3- (4- benzyloxy -3- fluorophenyls) -5- Qiang Jia Ji oxazolidine -2- ketone (1)
Formula (4) compound (25g, 0.071mol) is added in 250ml anhydrous tetrahydro furans.Two silicon of 1.0M hexamethyls is added dropwise
Base potassamide (74ml, 0.074mol), is cooled to less than 5 DEG C, add in R- (-)-Glycidyl Butyrate (10.8g,
0.0748mol).It is warmed to room temperature after stirring 1h, adds in the t-butanol solution 2ml stirring 15min of 20% tert-butyl alcohol lithium, add
The aqueous tartaric acid solution 23ml of 3M.By reaction solution vacuum rotary steam, add water (120ml, 5 volumes), filter, obtain crude white solid
(HPLC:Impurity a0.12%, impurity b8%).
Crude product obtains 18.05g white solids 1 with recrystallisation from isopropanol, is (5R) -3- (4- benzyloxy -3- fluorobenzene
Base) -5- Qiang Jia Ji oxazolidine -2- ketone (1), yield 80%.
Claims (10)
1. it is used to prepare the preparation method of click azoles amine key intermediate, which is characterized in that include the following steps：Formula (4) is changed
It closes object to act on non-nucleophilic highly basic, then be reacted with (R)-Glycidyl butyrate, reaction solution adds in nucleophilic examination at room temperature
The reactant aqueous solution of agent solution and acid then from reaction product, collects described formula (1) compound；Reaction expression is as follows：
2. according to the method described in claim 1, it is characterized in that, the non-nucleophilic highly basic is selected from two silicon substrate amido of hexamethyl
Potassium, sodium hexamethyldisilazide, hexamethyldisilazide lithium or lithium diisopropylamine.
3. according to the method described in claim 1, it is characterized in that, the nucleopilic reagent is selected from C1~C5Saturation fat alkoxide.
4. according to the method described in claim 3, it is characterized in that, the nucleopilic reagent is selected from potassium tert-butoxide, sodium tert-butoxide, uncle
Butanol lithium, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide.
5. according to the method described in claim 2, it is characterized in that, the nucleopilic reagent is selected from C1~C5Saturation fat alkoxide.
6. according to the method described in claim 5, it is characterized in that, the nucleopilic reagent is selected from potassium tert-butoxide, sodium tert-butoxide, uncle
Butanol lithium, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide.
7. according to the method described in claim 1, it is characterized in that, the acid is selected from C1~C4Aliphatic acid, tartaric acid, Malaysia
Acid, malonic acid, ethanedioic acid, adipic acid, sulfuric acid or hydrochloric acid.
8. according to claim 1~7 any one of them method, which is characterized in that the nucleopilic reagent and formula (4) compound
Molar ratio is 1:3~1:6, the sour molar ratio with formula (4) compound is 1:1.05~1:2, the concentration of aqueous solution of the acid
For 2~12mol/L.
9. according to the method described in claim 8, it is characterized in that, the mass fraction of the nucleopilic reagent solution is 20%-
30%.
10. according to claim 1~7 any one of them method, which is characterized in that formula (4) compound and non-nucleophilic is strong
Alkali acts on, and then reacts 0.25h~1.5h with (R)-Glycidyl butyrate at -10~10 DEG C, and reaction solution adds at room temperature
The aqueous solution of nucleopilic reagent solution and acid reacts 0.25~2h.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005023801A1 (en) * | 2003-09-03 | 2005-03-17 | Morphochem Aktiengesellschaft für kombinatorische Chemie | Intermediate products for producing oxazolidinone-quinolone hybrids |
| WO2005058888A2 (en) * | 2003-12-18 | 2005-06-30 | Morphochem Aktiengesellschaft für kombinatorische Chemie | Oxazolidinone-quinolone hybrid antibiotics |
| EP1958941A1 (en) * | 2007-02-14 | 2008-08-20 | Lipideon Biotechnology AG | Oxazolidinones and their use as hypocholesterolemic agents |
| CN102177156A (en) * | 2008-10-10 | 2011-09-07 | 特留斯治疗学公司 | Methods for preparing oxazolidinones and compositions containing them |
| CN103601724A (en) * | 2013-11-14 | 2014-02-26 | 暨南大学 | Novel oxazolidinone compound, as well as preparation method and application thereof |
| CN105820161A (en) * | 2015-01-08 | 2016-08-03 | 常州方楠医药技术有限公司 | Synthetic method of rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative |
-
2016
- 2016-11-08 CN CN201610980569.8A patent/CN108059624A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005023801A1 (en) * | 2003-09-03 | 2005-03-17 | Morphochem Aktiengesellschaft für kombinatorische Chemie | Intermediate products for producing oxazolidinone-quinolone hybrids |
| WO2005058888A2 (en) * | 2003-12-18 | 2005-06-30 | Morphochem Aktiengesellschaft für kombinatorische Chemie | Oxazolidinone-quinolone hybrid antibiotics |
| EP1958941A1 (en) * | 2007-02-14 | 2008-08-20 | Lipideon Biotechnology AG | Oxazolidinones and their use as hypocholesterolemic agents |
| CN102177156A (en) * | 2008-10-10 | 2011-09-07 | 特留斯治疗学公司 | Methods for preparing oxazolidinones and compositions containing them |
| CN103601724A (en) * | 2013-11-14 | 2014-02-26 | 暨南大学 | Novel oxazolidinone compound, as well as preparation method and application thereof |
| CN105820161A (en) * | 2015-01-08 | 2016-08-03 | 常州方楠医药技术有限公司 | Synthetic method of rivaroxaban intermediate 5-hydroxy methyl oxazolidinone derivative |
Non-Patent Citations (3)
| Title |
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| MARTINE GEHIN ET AL.: "Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection", 《INTERNATIONAL JOURNAL OF ANTIMICROBIAL AGENTS》 * |
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