CN103467260A - Preparation method of 4-difluoromethoxy-3-hydroxybenzaldehyde - Google Patents
Preparation method of 4-difluoromethoxy-3-hydroxybenzaldehyde Download PDFInfo
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- CN103467260A CN103467260A CN2012101888069A CN201210188806A CN103467260A CN 103467260 A CN103467260 A CN 103467260A CN 2012101888069 A CN2012101888069 A CN 2012101888069A CN 201210188806 A CN201210188806 A CN 201210188806A CN 103467260 A CN103467260 A CN 103467260A
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Abstract
A disclosed preparation method of 4-difluoromethoxy-3-hydroxybenzaldehyde comprises the following steps: in an organic solvent, in the presence of a catalyst tetrabutylammonium bromide, under the effect of an acid binding agent, performing a nucleophilic substitution reaction on a compound 2 and difluorochloromethane, wherein the reaction temperature is 60-120 DEG C, and the organic solvent is one or more of isopropanol, DMF and 1, 4-dioxane. The preparation method is high in product yield and applicable to industrialized production.
Description
Technical field
The present invention is specifically related to the preparation method of a kind of 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde.
Background technology
3-hydroxyl-4-difluoro-methoxy phenyl aldehyde is the important intermediate for preparing the phosphodiesterase 4 inhibitors roflumilast.The synthetic method of 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde normally makes with 0412 and fluorizating agent reaction.Can react with difluoromethyl because 0412 has two hydroxyls, therefore, in reactant, except the monosubstituted product of the 4-OH of needs, also have by product 3,4-difluoro-methoxy phenyl aldehyde (two replacement), generate.Due to disubstituted generation, make the yield of the monosubstituted product of 4-OH descend.
How to improve the mono-substituted productive rate of 4-OH, have many patents to report.As patent documentation US2008/15226, adopting chlorine difluoroacetic acid sodium is fluorizating agent, take sodium hydroxide as acid binding agent 120 ℃ of reacting by heating in DMF, reaction 2h, productive rate 44%.WO2004/94411, US2007/254913, EP2070913, be also that employing chlorine difluoroacetic acid sodium is fluorizating agent, the sodium hydroxide of take heats 55 ℃ as acid binding agent in DMF, reaction 16h, productive rate 24%.US2010/29728, WO2008/142542, WO2010/84402, be to take chlorodifluoromethane as fluorizating agent, salt of wormwood is acid binding agent, heats 75 ℃～85 ℃ in DMF with 0412, reaction 4.5h, productive rate 25%～30%.US5731477, WO2006/44528, Chauret Nathalie, Guay Daniel, Li Chun.etal.Bioorganic& Medicinal Chemistry Letters; Vol.12; Nb.16; (2002); P.2149-2152, Guay Daniel, Hamel Pierre, Blouin Marc.etl Bioorganic& Medicinal Chemistry Letters; Vol.12; Nb.11; (2002); P.1457-1462, Zheng Shilong, Kaur Gurpreet, etal.Journal of Medicinal Chemistry; Vol.51; Nb.24; (2008); P.7673-7688 the method for report is to take the chlorine methyl difluoroacetate as fluorizating agent, and the cesium carbonate of take is warmed up to 60 ℃～65 ℃ in DMF as acid binding agent, and productive rate is 20%～21%, and the main drawback of the method is that cost is high, and yield is low.It is catalyzer that WO2005/21515 adopts benzyltriethylammoinium chloride (TEBA), take chlorodifluoromethane as fluorizating agent, and in DMF, reaction prepares 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde.The weak point of these methods is that reaction conversion ratio is low, and productive rate is low, has a large amount of 0412s to reclaim, the recovery complexity of 0412, and aftertreatment is loaded down with trivial details.
Summary of the invention
Technical problem to be solved by this invention is in the preparation method in order to overcome existing 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde, reaction conversion ratio is low, products collection efficiency is low, the defects such as cost is high, and aftertreatment is loaded down with trivial details, and the preparation method of a kind of 3-hydroxyl-4-difluoro-methoxy phenyl aldehyde is provided.Preparation method's of the present invention products collection efficiency is higher, is suitable for suitability for industrialized production.
The invention provides the preparation method of a kind of 3-hydroxyl as shown in Equation 3-4-difluoro-methoxy phenyl aldehyde, it comprises the following step: in organic solvent, under the catalysis of normal-butyl bromination ammonium, under the effect of acid binding agent, compound 2 and chlorodifluoromethane are carried out to nucleophilic substitution reaction as follows, get final product; Temperature of reaction is 60～120 ℃; Described organic solvent is one or more in Virahol, DMF and Isosorbide-5-Nitrae-dioxane;
In the present invention, described preparation method preferably comprises the following step: acid binding agent and solution A are mixed, pass into dichlorodifluoromethane, at 60～120 ℃ of temperature, carry out nucleophilic substitution reaction, get final product; Wherein, solution A is that compound 2 and normal-butyl bromination ammonium are dissolved in the solution formed in organic solvent.Better, acid binding agent wherein is in batches (as 2～5 times, preferably 3 times) join in reaction solution, before passing into dichlorodifluoromethane, with solution A, mix for the 1st time, the 2nd time later for to mix with reaction solution after starting to pass into dichlorodifluoromethane, and the timed interval at every turn added is preferably 1～2 hour (preferably 1.5 hours).Minute add for 3 times fashionablely, add-on is preferably: being 0.8～1.3 times of equivalent of compound 2 (preferably 1.1 times) for the first time, is 0.2～0.5 equivalent (preferably 0.3 equivalent) of compound 2 for the second time, is 0.3～0.4 equivalent of compound 2 for the third time.
In the present invention, described organic solvent is preferably Virahol.Organic solvent can be 5～30ml/g with the volume mass ratio of compound 2.
In the present invention, described acid binding agent can be one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood and cesium carbonate, and preferably sodium hydroxide, can adopt the aqueous sodium hydroxide solution of mass percent 30% to participate in reaction.The equivalence ratio of described compound 2 and acid binding agent be preferably 1: 1.5～1: 2 better be 1: 1.5～1: 1.7, further preferably 1: 1.6～1: 1.7.
In the present invention, described compound 2 is preferably 1 with the mol ratio of normal-butyl bromination ammonium: (0.5%～5%), better is 1: (0.5～1.5%) (as 1: 1%).
In the present invention, the temperature of reaction is preferably 60～90 ℃.The time of reaction can, by till detecting this reaction and no longer carrying out, be preferably 8～13 hours.
Without prejudice to the field on the basis of common sense, above-mentioned each optimum condition, but arbitrary combination obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is: preparation method's of the present invention products collection efficiency is higher, is suitable for suitability for industrialized production.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or select according to catalogue.
Embodiment 1:3, the preparation of 4-Dihydroxy benzaldehyde
Thermometer is being housed, add vanillin food grade,1000.000000ine mesh (compound 1) in constant pressure funnel and churned mechanically 1000ml four-hole bottle (100.00g) and anhydrous methylene chloride (195ml), stirring at room is even, (0.70g), stirring at room is to the solid CL to add aluminum trichloride (anhydrous) (123.5g) and TEBA (triethyl benzyl ammonia chloride).Slowly evenly drip pyridine (170ml) at 0～5 ℃, slowly be warming up to backflow (46-48 ℃), after backflow 9h, temperature is down to below 10 ℃, regulate pH=2 (1000ml) with 20% hydrochloric acid, dichloromethane extraction (2 * 400ml) reclaims raw material, ethyl acetate for water (3 * 500ml) extraction.Merge organic phase, anhydrous sodium sulfate drying, remove solvent under reduced pressure, 40 ℃ of vacuum-dryings, obtain palm fibre white or yellow pressed powder 0412 (compound 2), productive rate 96.5%, fusing point: 152.5～153.1 ℃ (151～153 ℃ or 150～52 ℃ of bibliographical informations).MS (ESI
+): [M+H]: 139.04, HPLC:98% can be directly used in next step reaction.
The preparation of embodiment 2:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (5.00g, 36.2mmol, 1.0eq) and normal-butyl bromination ammonium (0.117g, 0.362mmol, 1%eq) be dissolved in Virahol (60ml), stirring at room 20min, add 30% sodium hydroxide solution (1.59g, 39.82mmol, 1.1eq), stirring at room 30min, slowly be warming up to 65 ℃, start to pass into chlorodifluoromethane, temperature remains on 60～65 ℃, 1.5h after add 30% sodium hydroxide (0.43g, 10.86mmol, 0.3eq), continue reaction, add again 30% sodium hydroxide solution (0.43g after 1.5h, 10.86mmol, 0.3eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 43.6%.MS(ESI
+)：M+H：189.0368。HPLC：98％。
The preparation of embodiment 3:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (5.00g, 36.2mmol, 1.0eq) and normal-butyl bromination ammonium (0.117g, 0.362mmol, 1%eq) be dissolved in Virahol (60ml), stirring at room 20min, add 30% sodium hydroxide solution (1.59g, 39.82mmol, 1.1eq), stirring at room 30min, slowly be warming up to 65 ℃, start to pass into chlorodifluoromethane, temperature remains on 70～75 ℃, 1.5h after add 30% sodium hydroxide (0.43g, 10.86mmol, 0.3eq), continue reaction, add again 30% sodium hydroxide solution (0.43g after 1.5h, 10.86mmol, 0.3eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 51%.MS(ESI
+)：M+H：189.0368。HPLC：98％
The preparation of embodiment 4:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (5.00g, 36.2mmol, 1.0eq) and normal-butyl bromination ammonium (0.117g, 0.362mmol, 1%eq) be dissolved in Virahol (60ml), stirring at room 20min, add 30% sodium hydroxide solution (1.59g, 39.82mmol, 1.1eq), stirring at room 30min, slowly be warming up to 65 ℃, start to pass into chlorodifluoromethane, temperature remains on 120 ℃, 1.5h after add 30% sodium hydroxide (0.43g, 10.86mmol, 0.3eq), continue reaction, add again 30% sodium hydroxide solution (0.43g after 1.5h, 10.86mmol, 0.3eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 47.3%.MS(ESI
+)：M+H：189.0368。HPLC：98％
The preparation of embodiment 5:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (13.8g, 0.1mol, 1.0eq) and normal-butyl bromination ammonium (0.322g, 1mmol, 1%eq) be dissolved in DMF (100ml), stirring at room 20min, add 30% sodium hydroxide solution (4.4g, 0.11mol, 1.1eq), stirring at room 30min, slowly be warming up to 65 ℃, start to pass into chlorodifluoromethane, temperature remains on 70～75 ℃, 1.5h after add 30% sodium hydroxide (1.2g, 0.03mol, 0.3eq), continue reaction, add again 30% sodium hydroxide solution (1.2g after 1.5h, 0.03mol, 0.3eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 48.2%.
1H-NMR(CDCl
3，400MHz)δ6.1(br?s，IH)，6.48-6.85(t，IH?OCHF
2)，7.26(d，IH)，7.44(d，IH)，7.55(s，IH)，9.91(s，IH)。MS(ESI
+)：M+H：189.0368。HPLC：98％。
The preparation of embodiment 6:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (5.00g, 36.2mmol, 1.0eq) and normal-butyl bromination ammonium (0.058g, 0.181mmol, 0.5%eq) be dissolved in Virahol (60ml), stirring at room 20min, add 30% sodium hydroxide solution (1.59g, 39.82mmol, 1.1eq), stirring at room 30min, slowly be warming up to 65 ℃, start to pass into chlorodifluoromethane, temperature remains on 70～75 ℃, 1.5h after add 30% sodium hydroxide (0.43g, 10.86mmol, 0.3eq), continue reaction, add again 30% sodium hydroxide solution (0.43g after 1.5h, 10.86mmol, 0.3eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 47.6%.
1H-NMR(CDCl
3，400MHz)δ6.1(br?s，IH)，6.48-6.85(t，IH?OCHF
2)，7.26(d，IH)，7.44(d，IH)，7.55(s，IH)，9.91(s，IH)。MS(ESI
+)：M+H：189.0368。HPLC：98％。
The preparation of embodiment 7:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (5.00g, 36.2mmol, 1.0eq) and normal-butyl bromination ammonium (0.585g, 1.81mmol, 5%eq) be dissolved in Virahol (60ml), stirring at room 20min, add 30% sodium hydroxide solution (1.59g, 39.82mmol, 1.1eq), stirring at room 30min, slowly be warming up to 65 ℃, start to pass into chlorodifluoromethane, temperature remains on 70～75 ℃, 1.5h after add 30% sodium hydroxide (0.43g, 10.86mmol, 0.3eq), continue reaction, add again 30% sodium hydroxide solution (0.43g after 1.5h, 10.86mmol, 0.3eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 49%.
1H-NMR(CDCl
3，400MHz)δ6.1(br?s，IH)，6.48-6.85(t，IHOCHF
2)，7.26(d，IH)，7.44(d，IH)，7.55(s，IH)，9.91(s，IH)。MS(ESI
+)：M+H：189.0368。HPLC：98％。
The preparation of embodiment 8:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (4.00g, 28.9mmol, 1.0eq) and normal-butyl bromination ammonium (0.448g, 1.39mmol, 5%eq) be dissolved in 1, in 4-dioxane (44.6ml), stirring at room 20min, temperature is raised to 65 ℃, add 30% sodium hydroxide solution (1.21g, 31.79mmol, 1.1eq), stirring at room 30min, slowly be warming up to 80 ℃, start to pass into chlorodifluoromethane, temperature remains on 80 ℃, 1.5h after add 30% sodium hydroxide (0.347g, 8.6mmol, 0.3eq), continue reaction, add again 30% sodium hydroxide solution (0.347g after 1.5h, 8.6mmol, 0.3eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 47.3%.
1H-NMR(CDCl
3，400MHz)δ6.1(br?s，IH)，6.48-6.85(t，IH?OCHF
2)，7.26(d，IH)，7.44(d，IH)，7.55(s，IH)，9.91(s，IH)。MS(ESI
+)：M+H：189.0368。HPLC：98％。
The preparation of embodiment 9:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (13.8g, 0.1mol, 1.0eq) and normal-butyl bromination ammonium (0.161g, 0.5mmol, 0.5%eq) be dissolved in DMF (100ml), stirring at room 20min, add 30% sodium hydroxide solution (3.2g, 0.8mol, 0.8eq), stirring at room 30min, slowly be warming up to 65 ℃, start to pass into chlorodifluoromethane, temperature remains on 70～75 ℃, add 30% sodium hydroxide (2.0g after 2h, 0.05mol, 0.5eq), continue reaction, add again 30% sodium hydroxide solution (1.6g after 1h, 0.04mol, 0.4eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 47.7%.
1H-NMR(CDCl
3，400MHz)δ6.1(br?s，IH)，6.48-6.85(t，IHOCHF
2)，7.26(d，IH)，7.44(d，IH)，7.55(s，IH)，9.91(s，IH)。MS(ESI
+)：M+H：189.0368。HPLC：98％.。
The preparation of embodiment 10:3-hydroxyl-4-difluoro-methoxy phenyl aldehyde
Compound 2 (5.00g, 36.2mmol, 1.0eq) and normal-butyl bromination ammonium (0.585g, 1.81mmol, 5%eq) be dissolved in Virahol (60ml), stirring at room 20min, add 30% sodium hydroxide solution (1.88g, 47.06mmol, 1.3eq), stirring at room 30min, slowly be warming up to 65 ℃, start to pass into chlorodifluoromethane, temperature remains on 120 ℃, add 30% sodium hydroxide (0.43g after 1h, 10.86mmol, 0.3eq), continue reaction, add again 30% sodium hydroxide solution (0.58g after 2h, 14.33mmol, 0.4eq), continue reaction 5～6h, temperature drops to 15 ℃, add the water termination reaction.Filter, remove solid residue, filtrate is extracted with ethyl acetate, and merges organic phase, be washed to neutrality, anhydrous sodium sulfate drying, steaming desolventizes, silica gel column chromatography (sherwood oil: ethyl acetate 5: 1), obtain white solid powder (compound 3), productive rate 48.3%.MS(ESI
+)：M+H：189.0368。HPLC：98％?。
Claims (10)
1. the preparation method of 3-hydroxyl as shown in Equation 3-4-difluoro-methoxy phenyl aldehyde, it is characterized in that comprising the following step: in organic solvent, under the catalysis of normal-butyl bromination ammonium, under the effect of acid binding agent, compound 2 and chlorodifluoromethane are carried out to nucleophilic substitution reaction as follows, get final product; Temperature of reaction is 60～120 ℃; Described organic solvent is one or more in Virahol, DMF and Isosorbide-5-Nitrae-dioxane;
2. preparation method as claimed in claim 1, it is characterized in that: described preparation method comprises the following step: acid binding agent and solution A are mixed, pass into dichlorodifluoromethane, at 60～120 ℃ of temperature, carry out nucleophilic substitution reaction, get final product; Wherein, solution A is that compound 2 and normal-butyl bromination ammonium are dissolved in the solution formed in organic solvent.
3. preparation method as claimed in claim 2, it is characterized in that: acid binding agent joins in reaction solution in batches, before passing into dichlorodifluoromethane, with solution A, mix for the 1st time, the 2nd time later for to mix with reaction solution after starting to pass into dichlorodifluoromethane, and the timed interval at every turn added is 1～2 hour.
4. preparation method as claimed in claim 3, it is characterized in that: acid binding agent divides 3 times to add fashionable, add-on is: being 0.8～1.3 times of equivalent of compound 2 for the first time, is 0.2～0.5 equivalent of compound 2 for the second time, is 0.3～0.4 equivalent of compound 2 for the third time.
5. preparation method as claimed in claim 4 is characterized in that: acid binding agent divides and adds for 3 times fashionablely, and add-on is: being 1.1 times of equivalents of compound 2 for the first time, is 0.3 times of equivalent of compound 2 for the second time.
6. preparation method as described as claim 1～5 any one, it is characterized in that: described acid binding agent is one or more in sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood and cesium carbonate.
7. preparation method as described as claim 1～5 any one is characterized in that: described compound 2 is 1: 1.5～1: 2 with the equivalence ratio of acid binding agent.
8. preparation method as described as claim 1～5 any one is characterized in that: described compound 2 is 1 with the mol ratio of normal-butyl bromination ammonium: (0.5%～5%).
9. preparation method as claimed in claim 8 is characterized in that: described compound 2 is 1 with the mol ratio of normal-butyl bromination ammonium: (0.5～1.5%).
10. preparation method as described as claim 1～5 any one, it is characterized in that: the temperature of reaction is 60～90 ℃.
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| CN106379644A (en) * | 2016-11-15 | 2017-02-08 | 苏州亨达尔工业材料有限公司 | Shockproof and anti-impact hollow board |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005021515A2 (en) * | 2003-08-29 | 2005-03-10 | Ranbaxy Laboratories Limited | Inhibitors of phosphodiesterase type-iv |
| WO2008035316A2 (en) * | 2006-09-22 | 2008-03-27 | Ranbaxy Laboratories Limited | Phosphodiesterase inhibitors |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005021515A2 (en) * | 2003-08-29 | 2005-03-10 | Ranbaxy Laboratories Limited | Inhibitors of phosphodiesterase type-iv |
| WO2008035316A2 (en) * | 2006-09-22 | 2008-03-27 | Ranbaxy Laboratories Limited | Phosphodiesterase inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| 钟永刚等: "罗氟司特的合成", 《中国医药工业杂志》, vol. 42, no. 12, 31 December 2011 (2011-12-31), pages 884 - 886 * |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106379644A (en) * | 2016-11-15 | 2017-02-08 | 苏州亨达尔工业材料有限公司 | Shockproof and anti-impact hollow board |
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