CN109265408B - Synthesis method of difluoromethyl substituted oxan-2-ketone - Google Patents
Synthesis method of difluoromethyl substituted oxan-2-ketone Download PDFInfo
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
- C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D265/10—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen atoms directly attached to ring carbon atoms
Abstract
The invention relates to a synthesis method for preparing difluoromethyl substituted dioxane-2-ketone, which takes a compound III as a raw material and prepares the difluoromethyl substituted dioxane-2-ketone by two steps of reactions of fluorination and deprotectionPreparing a compound I; the method has the advantages of simple and convenient operation, easy monitoring of reaction, short synthesis period, high yield, low risk and low cost, and is suitable for industrial production;
Description
Technical Field
The invention relates to a synthetic method of difluoromethyl substituted dioxane-2-ketone, belonging to the field of organic synthesis.
Background
The 4,4- (difluoromethyl) oxazolidine-2-ketone is used as an intermediate for preparing a benzooxazepine oxazolidinone compound with phosphoinositide-3 kinase regulating activity or function, and the synthesis method of the 4,4- (difluoromethyl) oxazolidine-2-ketone disclosed by WO2017001645A1 and WO2017001658A1 is shown as the following formula, and the compound is prepared by using a compound 1 as a raw material through oxidation, fluorination, deprotection, two-step selective protection, sodium azide substitution, reduction, deprotection and cyclization 9-step reaction. The inventor finds that the compound 2 is unstable and has strong volatility, and can be stably stored for only 4 to 5 days under the condition of argon filling at the temperature of-20 ℃; and the purity of the compound 2 has a large influence on the fluorination reaction, the inventor finds that when the purity of the compound 2 is less than 80%, the nuclear magnetic monitoring fluorination reaction is very disordered to prepare the compound 3, and the yield of the compound 3 obtained after purification is less than 30%; in order to improve the yield of the fluorination reaction, the pure compound 2 needs to be prepared by rectification and purification, but the loss in the purification process is large. The compound 3 can not be detected by thin-layer chromatography and liquid chromatography, so that the fluorination reaction is not easy to control. In addition, when compound 7 is prepared from compound 6, highly dangerous sodium azide is used, and the introduced azide group needs to be reduced to an amino group by hydrogenation using an expensive palladium catalyst. In conclusion, the existing method for preparing 4,4- (difluoromethyl) oxazolidine-2-ketone has the problems of high reaction risk, long reaction period, difficulty in central control and storage, high cost, poor atom economy and the like, and is not suitable for industrial production.
Disclosure of Invention
The invention aims to provide a safe and simple preparation method of difluoromethyl substituted dioxane-2-ketone and a stereoisomer, a hydrate and a solvate thereof.
In order to solve the above technical problems, the technical solution adopted by the present invention can be represented by the following procedures:
wherein n is 1,2, 3;
(1) and step 1, preparing a compound II from the compound III under the action of a fluorination reagent. The fluorinating agent is selected from diethylaminosulfur trifluoride (DAST), N-diethyl-S, S-difluoro-sulfilimidium tetrafluoroborate (XtalFluor-E), XtalFluor-E \ pyridine hydrogen fluoride, XtalFluor-E \ triethylamine trihydrofluoride, bis (2-methoxyethyl) aminosulfur trifluoride (BAST), 4-tert-butyl-2, 6-dimethylphenylsulfur trifluoride, dimethylaminosulfur trifluoride or 2, 2-difluoro-1, 3-benzodioxole, preferably DAST or BAST; the feeding molar ratio of the fluorination reagent to the compound III is 1-2.5: 1; suitable organic solvents for the reaction are selected from one or more of dichloromethane, ethanol, methanol, acetonitrile, carbon tetrachloride, ethylene glycol, 1, 2-dichloroethane, 1, 4-dioxane, toluene, benzene, DMF or THF, preferably one or two of dichloromethane or toluene; the temperature suitable for the reaction is 0-35 ℃; furthermore, the temperature of the reaction solution is controlled not to exceed 10 ℃ when the fluorinating agent is added.
The reaction can be conveniently monitored and controlled by a phosphomolybdic acid chromogenic method. By-products such as monofluoro or ectopic difluoro are not detected in the fluoro reaction;
after the fluorination reaction is finished, controlling the temperature in the reaction solution to be lower than 40 ℃ to quench the reaction, adding a first organic solvent for extraction, combining organic phases for drying, filtering and concentrating, and separating by fast column chromatography to obtain a crude compound II; the obtained crude compound II can be pulped in a second organic solvent to prepare a white solid compound II with the purity of 99 percent; the first organic solvent is one or more of dichloromethane, ethyl acetate, toluene, benzene, THF or DMF; the second organic solvent is selected from one or more of methyl tertiary ether, petroleum ether, n-hexane or n-heptane.
The compound III can be prepared according to the method disclosed in US20070004728 for 2-oxo-3- (triphenylmethyl) -1, 3-oxazolidine-4-formaldehyde.
(2) And 2, carrying out deprotection reaction on the compound II under the action of a deprotection reagent to prepare a compound I. The inventors found that trityl group could not be removed by using citric acid, formic acid, acetic acid, phosphoric acid, chloroacetic acid, benzoic acid, etc.; suitable deprotecting reagents for step 2 are selected from one or more of trifluoroacetic acid, trichloroacetic acid, hydrochloric acid or sulfuric acid, preferably hydrochloric acid, more preferably hydrochloric acid gas, aqueous hydrochloric acid solution or hydrochloric acid in dioxane; suitable solvents for the deprotection reaction are selected from one or more of dichloromethane, ethanol, methanol, acetonitrile, carbon tetrachloride, ethylene glycol, ethyl acetate, 1, 2-dichloroethane, 1, 4-dioxane, toluene, benzene, DMF, THF or water, preferably one or more of dichloromethane, methanol or ethanol; the temperature suitable for the deprotection reaction is 0-50 ℃. After the reaction is finished, the post-treatment method comprises the steps of cooling the reaction liquid to room temperature, concentrating at low temperature and then separating by fast column chromatography.
The invention has the advantages that:
1. the invention discloses a synthetic method for preparing difluoromethyl substituted dioxane-2-ketone, which avoids using sodium azide and expensive palladium hydroxide/carbon, greatly reduces the risk and saves the cost;
2. the method disclosed by the invention can be used for conveniently carrying out central control monitoring on the fluoro reaction, and the controllability of the reaction is improved.
3. Compared with the prior art, the method disclosed by the invention has the advantages that the reaction steps are reduced, the synthesis period is shortened, and the reaction cost is reduced; the method disclosed by the invention has the advantages of high overall yield, increased atom economy, simple and convenient post-treatment, successful development of preparation of hectogram-level difluoromethyl substituted dioxane-2-ketone, high yield of two steps up to 82%, and suitability for industrial scale-up production.
Detailed Description
The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Operations or steps not specifically indicated in the following examples are generally carried out according to conventional conditions in the art.
The starting materials or reagents used in the examples are, unless otherwise specified, commercially available.
The room temperatures stated in the examples are all 5-35 ℃. Unless otherwise indicated, the reagents were used without purification and all solvents were purchased from commercial suppliers. The reaction was judged for termination by TLC analysis and/or by LC-MS analysis by consumption of starting material. Thin Layer Chromatography (TLC) for analysis was performed on glass plates (EMD Chemicals) precoated with silica gel 60F 2540.25 mm plates, developed with UV light (254nm) and/or iodine on silica gel, and/or heated with TLC stains such as alcoholic phosphomolybdic acid, ninhydrin solution, potassium permanganate solution, or ceric sulfate solution.
1H-NMR spectra were recorded on a Varian Mercury-VX400 instrument at 400MHz operation.
Abbreviations used in the present invention have conventional meanings in the art. Wherein DMF represents N, N-dimethylformamide, THF represents tetrahydrofuran, TBS represents tert-butyldimethylsilyl, Tf represents trifluoromethanesulfonic group, Trt represents trityl, DAST represents diethylaminosulfur trifluoride, XtalFluor-E represents N, N-diethyl-S, S-difluoro-sulfilimidium tetrafluoroborate, BAST represents bis (2-methoxyethyl) aminosulfur trifluoride, PE represents petroleum ether, EA represents ethyl acetate, and DCM represents dichloromethane.
Preparation of the starting Material
1. Preparation of (S) -2-oxo-3-trityl oxazolidine-4-carbaldehyde
Step (1), preparation of N-trityl-L-serine methyl ester
L-serine methyl ester hydrochloride (300g, 1.93mol) was dispersed in dichloromethane (2.5L), triethylamine (391g, 3.86mol) was added, a dichloromethane solution (1.5L) of triphenylchloromethane (541g, 1.93mol) was added dropwise while controlling the internal temperature at 0 to 10 ℃, and the mixture was allowed to warm to room temperature after completion of the addition and reacted overnight. The reaction mixture was slowly poured into saturated brine (2L), and after separation by stirring, the organic phase was separated, and water phase was added and extracted with DCM (2X 1L), and the organic phases were combined and washed with saturated sodium chloride (2L), dried over anhydrous sodium sulfate, concentrated, and dried by suction to give N-trityl-L-serine methyl ester (590g, yield 84.5%) as a white solid.
Step (2), (S) -2-oxo-3-trityl oxazolidine-4-carboxylic acid methyl ester preparation
Dissolving N-trityl-L-serine methyl ester (560g, 1.55mol) in toluene (4L), adding triethylamine (260g, 2.57mol), dropwise adding a toluene (2L) solution of triphosgene (506g, 1.70mol) under an ice bath condition, raising the temperature to room temperature after the dropwise adding is finished, reacting overnight, and detecting the completion of the reaction by TLC. Cooling the reaction liquid to below 10 ℃, slowly dropwise adding saturated sodium carbonate aqueous solution to adjust the pH value to 7, then adding EA (2L) for extraction, washing an organic phase by using the saturated sodium carbonate aqueous solution (2L) and sodium chloride aqueous solution (2L) in turn, drying by using anhydrous sodium sulfate, concentrating, draining to obtain a white solid crude product, adding a PE/EA mixed solution (1L, PE: EA ═ 3:1) for pulping, filtering, and drying to obtain a pure product (S) -2-oxo-3-trityl oxazolidine-4-carboxylic acid methyl ester (534g, yield 89%).
Step (3), (S) -2-oxo-3-trityl oxazolidine-4-carbaldehyde
Dissolving (S) -2-oxo-3-trityl oxazolidine-4-carboxylic acid methyl ester (200g, 0.51mmol) in THF (4L), slowly adding lithium aluminum hydride (23g, 0.60mmol) at the internal temperature of less than-30 ℃ under the protection of inert gas, reacting for 2h, and monitoring the reaction completion by TLC. Heating the reaction solution to-10-0 ℃, slowly adding EA (23ml), stirring for 15min, sequentially and slowly adding water (23ml), a 20% NaOH aqueous solution (23ml) and water (69ml), stirring for 0.5h, adding magnesium sulfate (50g), stirring for 0.5h, filtering, concentrating, washing a filter cake with ethyl acetate, combining the filtrates, and concentrating to obtain a white jelly (195 g).
The resulting white gum was dissolved in DCM (3L) and dess-martin oxidant (262.6g, 0.62mol) was added to the reaction mixture at a temperature of less than 20 deg.C and allowed to react overnight at room temperature. Cooling the reaction solution to 15-20 ℃, adding a sodium thiosulfate solution (3.5L), stirring for half an hour, layering, adding DCM (500ml multiplied by 2) into water phase for extraction, combining organic phases, washing with a saturated sodium carbonate aqueous solution (500ml) and a saturated saline solution (600ml) in sequence, drying with anhydrous sodium sulfate, filtering and concentrating, pulping the obtained crude product in petroleum ether, filtering and drying to obtain (S) -2-oxo-3-trityl oxazolidine-4-formaldehyde (170g, 93.2%, wherein the nuclear magnetic characterization information of the (S) -2-oxo-3-trityl oxazolidine-4-formaldehyde is consistent with the published characterization information in US 20070004728).
2. Preparation of (R) -2-oxo-3-trityl oxazolidine-4-carbaldehyde
Prepared according to the preparation method of (S) -2-oxo-3-trityl oxazolidine-4-formaldehyde1H-NMR(CDCl3,400MHz)9.21(d,1H,J＝3.1Hz),7.34(m,15H),4.49(dd,1H,J＝9.5,9.5Hz),4.35(ddd,1H,J＝3.1,4.5,9.5Hz),4.19(dd,1H,J＝4.5,9.2Hz))。
3. Preparation of (S) -2-oxo-3-trityl-1, 3-oxazinane-4-carbaldehyde
Prepared according to the preparation method of (S) -2-oxo-3-trityl oxazolidine-4-formaldehyde1H-NMR(CDCl3,400MHz)9.41(d,1H,J＝3.1Hz),7.32(m,15H),4.52-3.90(m,3H),2.30-1.80(m,2H))。
Example 1:
step (1): preparation of (S) -4- (difluoromethyl) -3-trityloxazolidin-2-one
Dissolving (S) -2-oxo-3-trityl oxazolidine-4-formaldehyde (500g, 1.27mol) in DCM (10L) at room temperature, cooling the reaction liquid under the protection of inert gas, controlling the reaction temperature to be not more than 10 ℃, slowly injecting DAST (253ml, 1.9mol), heating to 30-35 ℃ for reaction after adding, silica gel plate phosphomolybdic acid color development monitoring reaction, after the reaction is finished, slowly pouring the reaction liquid into ice saturated sodium bicarbonate water solution (8L), controlling the dropping speed and the internal temperature to be less than 40 ℃, stirring and layering after quenching is finished, adding dichloromethane (3L × 3) into a water phase for extraction, combining organic phases, washing (2.5 × 2L) with saturated sodium chloride, drying with anhydrous sodium sulfate, filtering and concentrating, quickly separating (PE: EA: 10: 1-2: 1) to prepare 470g of crude product, pulping the crude product in methyl tert-ether (500ml), filtering and extracting to obtain a white solid (S) -4- (difluoromethyl oxazolidine) -3-methyl oxazolidine-4- (difluoro methyl oxazolidine) by dry column chromatography-2-ketone (438g, 91% yield, 99% purity,1H-NMR(CDCl3，400Hz)7.39-7.25(m,15H)，4.90-4.55(m,2H)，4.46-4.41(t,1H)，4.17-4.08(m,1H))。
step (2): preparation of (S) -4- (difluoromethyl) oxazolidin-2-ones
At room temperature, (S) -4- (difluoromethyl) -3-trityl oxazolidin-2-one (369g, 0.97mol) was dissolved in methanol (4L), hydrochloric acid/dioxane (4N, 2L) solution was added, the temperature was raised to 50 ℃ for reaction, and the reaction was monitored by silica gel plate phosphomolybdic acid color development. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated to remove the solvent, and dissolved in dichloromethane (5ml), and then subjected to silica gel column chromatography (DCM: MeOH ═ 20:1) by wet chromatography to give (S) -4- (difluoromethyl) oxazolidin-2-one (120g, yield 90%,1H-NMR(CDCl3，400Hz)6.08(s，2H)，5.93-5.64(m，1H)，4.92-4.36(m，2H)，4.14-4.00(m，1H))。
example 2:
step (1): preparation of (R) -4- (difluoromethyl) -3-trityloxazolidin-2-one
Dissolving (R) -2-oxo-3-trityl oxazolidine-4-formaldehyde (2g, 5.59mmol) in toluene (20ml) at room temperature, cooling the reaction solution under the protection of inert gas, controlling the reaction temperature to be not more than 10 ℃, slowly injecting BAST (2.5ml, 13.98mmol), raising the temperature to 35 ℃ after the addition is finished, reacting, and monitoring the reaction by silica gel plate phosphomolybdic acid color development. After completion of the reaction, a white solid, (R) -4- (difluoromethyl) -3-trityl oxazolidin-2-one (1.91g, 90% yield, ESI/MS: M/z 381(M + H) was prepared according to the workup procedure of example 4+)。
Step (2): preparation of (R) -4- (difluoromethyl) oxazolidin-2-ones
At room temperature, (R) -4- (difluoromethyl) -3-trityl oxazolidin-2-one (1.9g, 5.00mmol) was dissolved in dichloromethane (20ml), hydrochloric acid gas was introduced, and stirring was continued until the color development monitoring reaction of silica gel plate phosphomolybdic acid was completed. The reaction mixture was concentrated to remove the solvent, and after dissolving in dichloromethane (2ml), wet-loading was carried out on silica gel column chromatography (DCM: MeOH ═ 20:1) to give (R) -4- (difluoromethyl) oxazolidin-2-one (617mg, yield 90%, ESI/MS: M/z ═ 138(M + H) as a yellow oil+)。
Example 3:
step (1): preparation of (S) -4- (difluoromethyl) -3-trityl-1, 3-oxazinan-2-one
Under the ice bath condition, (S) -2-oxo-3-trityl-1, 3-oxazinane-4-formaldehyde (1g, 2.69mmol) is dissolved in toluene (5ml) and dichloromethane (5ml), under the protection of inert gas, the reaction liquid is cooled, the reaction temperature is controlled not to exceed 10 ℃, DAST (0.35ml, 2.69mmol) is slowly injected, after the addition is finished, the temperature is raised to the room temperature, and the mixture is stirred until the color development of phosphomolybdic acid of a silica gel plate is monitored and the reaction is completed. After completion of the reaction, white solid (S) -4- (difluoromethyl) -3-trityl-1, 3-oxazinan-2-one (900mg, yield 85%, ESI/MS: M/z ═ 394(M + H) was prepared according to the workup procedure of example 4+)。
Step (2) preparation of (S) -4- (difluoromethyl) -1, 3-oxazinan-2-one
Under the ice-bath condition, (S) -4- (difluoromethyl) -3-trityl-1, 3-oxazinan-2-one (900mg, 2.29mmol) is dissolved in ethanol (10ml), aqueous hydrochloric acid (4N, 5.7ml) is added, the temperature is raised to 50 ℃, and stirring is continued until the color development of silica gel plate phosphomolybdic acid monitors the reaction to be completed. The reaction mixture was cooled to room temperature, concentrated to remove the solvent, dissolved in methylene chloride (1.5ml), and subjected to silica gel column chromatography by wet loading(DCM: MeOH ═ 20:1) was isolated as (S) -4- (difluoromethyl) -1, 3-oxazinan-2-one (294mg, 85% yield, ESI/MS: M/z ═ 152(M + H) as a yellow oil+)。
Comparative example 1: preparation of (S) -4- (difluoromethyl) oxazolidin-2-ones
Dissolving (S) -4- (difluoromethyl) -3-trityl oxazolidine-2-ketone (500mg, 1.32mmol) in ethanol (5ml) at room temperature, adding acetic acid (1.1ml, 19.8mmol), heating to 50 ℃ for reaction, and monitoring the reaction by silica gel plate phosphomolybdic acid color development respectively in 0.5h, 1h and 2h, wherein the generation of a deprotection product is not monitored; the reaction system is heated to reflux and stirred overnight, and the silica gel plate phosphomolybdic acid is developed and the liquid chromatography does not detect the generation of (S) -4- (difluoromethyl) oxazolidin-2-ketone.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (8)
1. A synthetic method for preparing difluoromethyl substituted oxan-2-ketone compound I is characterized by comprising the following steps,
step 1, preparing a compound III in an organic solvent under the action of a fluorinating reagent to obtain a compound II,
step 2, carrying out deprotection reaction on the compound II under the action of a deprotection reagent to prepare a compound I,
wherein n is 1,2, 3;
in the step 1, the fluorinating reagent is selected from diethylaminosulfur trifluoride or bis (2-methoxyethyl) aminosulfur trifluoride; the feeding molar ratio of the fluorination reagent to the compound III is 1-2.5: 1; the organic solvent is selected from one or more of dichloromethane, ethanol, methanol, acetonitrile, carbon tetrachloride, ethylene glycol, 1, 2-dichloroethane, 1, 4-dioxane, toluene, benzene, DMF and THF; the temperature suitable for the reaction is 0-35 ℃;
in the step 2, the deprotection reagent is selected from one or more of trifluoroacetic acid, trichloroacetic acid, hydrochloric acid, hydrogen chloride gas, a solution of hydrogen chloride in dioxane or sulfuric acid; the solvent for deprotection reaction is selected from one or more of dichloromethane, ethanol, methanol, acetonitrile, carbon tetrachloride, ethylene glycol, ethyl acetate, 1, 2-dichloroethane, 1, 4-dioxane, toluene, benzene, DMF, THF or water; the deprotection reaction temperature is 0-50 ℃.
2. The method of synthesizing compound I according to claim 1, wherein the temperature of the reaction solution during the addition of the fluorinating agent in step 1 does not exceed 10 ℃.
3. The method for synthesizing the compound I according to claim 1, wherein in the step 1, after the reaction is finished, the reaction is quenched, a first organic solvent is added for extraction, the organic phases are combined for drying, filtration and concentration are carried out, and a crude compound II is prepared by flash column chromatography separation; pulping the obtained crude compound II in a second organic solvent to obtain a high-purity pure compound II.
4. The method for synthesizing compound I according to claim 3, wherein the first organic solvent is one or more selected from dichloromethane, ethyl acetate, toluene, benzene, THF or DMF; the second organic solvent is selected from one or more of methyl tertiary ether, petroleum ether, n-hexane or n-heptane.
5. The method for synthesizing the compound I according to claim 1, wherein in the step 1, the organic solvent suitable for the reaction is one or two of dichloromethane or toluene.
6. The method of synthesizing compound I according to claim 1, wherein in step 2, the deprotecting reagent is hydrochloric acid.
7. The method of claim 1, wherein in step 2, the deprotection reagent is hydrogen chloride gas or a solution of hydrogen chloride in dioxane.
8. The method for synthesizing the compound I according to claim 1, wherein in the step 2, the solvent for the deprotection reaction is selected from one or more of dichloromethane, methanol or ethanol.
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