CN106883118A - A kind of synthetic method of roflumilast key intermediate - Google Patents

A kind of synthetic method of roflumilast key intermediate Download PDF

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CN106883118A
CN106883118A CN201710075456.8A CN201710075456A CN106883118A CN 106883118 A CN106883118 A CN 106883118A CN 201710075456 A CN201710075456 A CN 201710075456A CN 106883118 A CN106883118 A CN 106883118A
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difluoro
methoxyl group
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methoxy
synthetic method
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王祥
尚慕宏
王利
张峰
余夙
龚亚东
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Taicang Enkang Medicine Science And Technology Co Ltd
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Taicang Enkang Medicine Science And Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/27—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with oxides of nitrogen or nitrogen-containing mineral acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/78—Separation; Purification; Stabilisation; Use of additives
    • C07C45/81—Separation; Purification; Stabilisation; Use of additives by change in the physical state, e.g. crystallisation

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Abstract

The invention discloses a kind of synthetic method of roflumilast key intermediate.Specifically, the synthetic method comprises the following steps：1) the difluoro-methoxy benzaldehyde of 3 methoxyl group 4 is prepared；2) the difluoro-methoxy benzaldehyde of 3 hydroxyl 4 is prepared；3) the difluoro-methoxy benzaldehyde of 3 the third methoxyl group of ring 4 is prepared；4) difluoro-methoxy-benzoic acid of 3 the third methoxyl group of ring 4 is prepared.Compared in existing synthetic method, the cheap raw material of the method selection in the present invention greatly reduces production cost；With vanillic aldehyde as initiation material, it is to avoid the generation of similar impurity；Replace column chromatography as means of purification to recrystallize, be conducive to large-scale production and application, and with yield and purity higher.

Description

A kind of synthetic method of roflumilast key intermediate
Technical field
The invention belongs to technical field of medicine synthesis, it is related to a kind of the third methoxyl group of roflumilast key intermediate 3- rings -4- The synthetic method of difluoro-methoxy-benzoic acid.
Background technology
Roflumilast (Roflumilast), chemical name be N- (3,5- dichloropyridine -4- bases) -3- (methoxyl group of ring third) - 4- (difluoro-methoxy) benzamide, belongs to phosphodiesterase-4 (PDE-4) inhibitor, can be blocked with Selective depression PDE-4 Inflammatory reaction signal transmission, and then suppress the damage that such as COPD and asthma breathing problem are caused to lung tissue, it is a kind of new The COPD medicines of type.
In the building-up process of roflumilast, key intermediate 3- ring the third methoxyl group -4- difluoro-methoxy-benzoic acids are to work as One of key factor of preceding restriction industrialized production.At present, the synthesis of the third methoxyl group of 3- rings -4- difluoro-methoxy-benzoic acids is main It with vanillic aldehyde is the raw material that sets out to be, by methyl deprotection reaction, twice coupling reaction and aldehyde radical oxidation reaction, is finally obtained Target product.
In coupling reaction twice, existing most of documents or patent are all preferentially coupled difluoro-methoxy, then are coupled ring Hydroxypropyl methyl, wherein difluoro-methoxy coupling reaction are to cause whole Product industrialization difficult and cost increase key factor. In addition, regardless of two kinds of sequencings of substitution base coupling reaction, when the first substitution base is coupled, all can be because of reaction bottom Two selecting response sex differernces of phenolic hydroxyl group present in thing structure less cause a large amount of generations of similar impurity, subsequently can only The method purified by column chromatography is purified, and is constrained technique industrialization in itself and is expanded, and substantially reduces yield.This Outward, when difluoro-methoxy is coupled, it usually needs use difluoro sodium chloroacetate, the cost of material costly, to cause cost Steeply rise.Therefore, new synthetic route has been used in US2008/0306027 A1, with vanillic aldehyde as raw material, first with cost Cheap difluorochloromethane carries out 4 couplings, then spent glycol is protected aldehyde radical, then sloughs 3 methoxyl groups, then slough The blocking group of aldehyde radical, finally gives the product of single coupling.However, the route needs to use the more expensive phase transfer catalysis (PTC) of price Agent (PTC) 18- crown- 6- ethers, boron trifluoride ether solution and diphenylphosphide lithium, cause cost to increase, and produced three It is useless that considerable influence easily is produced to environment, it is unfavorable for large-scale production.
The content of the invention
For cost of material present in existing the third methoxyl group of 3- rings -4- difluoro-methoxy-benzoic acid synthetic methods it is high, The problems such as impurity serious interference, aftertreatment technology are complicated, yield is low, industrialization promotion difficulty is big, the present invention uses new synthesis Route, equally with vanillic aldehyde as raw material, first carries out the difluoro-methoxy coupling reaction on 4, in reselection ground removing 3 Methoxyl group is protected, and by being recrystallized to give difluoro-methoxy mono-substituted products, the methoxyl group of ring third coupling then carried out on 3 is anti- Should and aldehyde radical oxidation reaction, finally give target product 3- ring the third methoxyl group -4- difluoro-methoxy-benzoic acids.
Specifically, the present invention is adopted the following technical scheme that：
A kind of synthetic method of roflumilast key intermediate, it comprises the following steps：
1) 3- methoxyl group -4- difluoro-methoxy benzaldehydes are prepared：
To the vanillic aldehyde, reaction dissolvent and acid binding agent that are added in reaction vessel as shown in Formula II, under agitation will be upper The system of stating is heated to 80~100 DEG C, then passes to monochlorodifluoromethane, and vanillic aldehyde stops heating, adds water and be quenched after reacting completely Extracted with organic solvent after reaction, organic phase is scrubbed, dry, concentration, obtains the 3- methoxyl group -4- difluoros as shown in formula III Methoxybenzaldehyde；
2) 3- hydroxyl -4- difluoro-methoxy benzaldehydes are prepared：
To adding step 1 in reaction vessel) in the 3- methoxyl group -4- difluoromethoxy phenyl first as shown in formula III that obtains Aldehyde, reaction dissolvent and lithium salts, are heated to backflow, 3- methoxyl group -4- difluoromethoxy phenyl first by above-mentioned system under agitation Aldehyde stops heating after reacting completely, regulation pH value is extracted to after 1~2 with organic solvent, and organic phase is scrubbed, drys, concentration, weigh Crystallization, obtains the 3- hydroxyl -4- difluoro-methoxy benzaldehydes as shown in formula IV；
3) 3- ring the third methoxyl group -4- difluoro-methoxy benzaldehydes are prepared：
To in reaction vessel add step 2) in obtain the 3- hydroxyl -4- difluoro-methoxies benzaldehyde as shown in formula IV, Reaction dissolvent and acid binding agent, above-mentioned system is stirred at room temperature, and is subsequently adding bromomethyl cyclopropane, 3- hydroxyl -4- difluoromethoxies Benzaldehyde adds water after reacting completely and reaction is quenched, and is then extracted with organic solvent, and organic phase is scrubbed, dry, concentration, obtains 3- rings the third methoxyl group -4- difluoro-methoxy benzaldehydes shown as a formula V；
4) 3- ring the third methoxyl group -4- difluoro-methoxy-benzoic acids are prepared：
To adding step 3 in reaction vessel) in 3- rings the third methoxyl group -4- difluoromethoxy phenyls shown as a formula V for obtaining Formaldehyde and acetic acid, above-mentioned system is stirred at room temperature, and is subsequently adding sulfamic acid, and chlorous acid is added after being cooled to 5~10 DEG C Sodium water solution, is then warmed to room temperature reaction, and 3- rings the third methoxyl group -4- difluoro-methoxy benzaldehydes add water after reacting completely and are quenched instead Should, agitated, filtering, washing, dry, obtain the methoxyl group of 3- rings third shown in formula I as roflumilast key intermediate- 4- difluoro-methoxy-benzoic acids.
In above-mentioned synthetic method, step 1) described in reaction dissolvent be selected from DMF (DMF), toluene (TOL) any one in, preferably DMF.
In above-mentioned synthetic method, step 1) described in acid binding agent be selected from NaOH (NaOH), potassium hydroxide (KOH), Potassium carbonate (K2CO3) in any one, preferably NaOH.
In above-mentioned synthetic method, step 2) described in reaction dissolvent be selected from DMF (DMF), toluene (TOL) any one in, preferably DMF.
In above-mentioned synthetic method, step 2) described in lithium salts be selected from appointing in lithium chloride (LiCl), lithium bromide (LiBr) Meaning is a kind of, preferably LiCl.
In above-mentioned synthetic method, step 2) described in recrystallize using ethyl acetate/n-hexane, isopropanol/n-hexane In any one, ethyl acetate/n-hexane.
In above-mentioned synthetic method, step 3) described in reaction dissolvent be selected from tetrahydrofuran (THF), dichloromethane (DCM) In any one, preferably THF.
In above-mentioned synthetic method, step 3) described in acid binding agent be selected from potassium carbonate (K2CO3), NaOH (NaOH), hydrogen Any one in potassium oxide (KOH), preferably K2CO3。
In above-mentioned synthetic method, step 4) described in sodium chlorite aqueous solution sodium chlorite mass percent concentration It is 15%~25%, preferably 20%.
Compared with prior art, there are following advantages using the present invention of above-mentioned technical proposal：
1) in existing synthetic route, usually using expensive difluoro sodium chloroacetate as difluoromethyl source Or 18- crown- 6- ethers or boron trifluoride ether solution using price costly, and synthetic method of the invention is then all selected With cheap raw material, production cost is greatly reduced；
2) when difluoro sodium chloroacetate and 3,4- 4-dihydroxy benzaldehyde react, the presence of two active phenolic hydroxyl groups is led in structure The selectivity reduction of reaction is caused, product is not easily purified, it usually needs purified using column chromatography, yield is low and is unfavorable for industrialization, And synthetic method of the invention only exists a phenolic hydroxyl group using vanillic aldehyde as initiation material, in structure, it is to avoid similar impurity Generation, column chromatography can be replaced using recrystallization during purifying so that whole process advan expands in industrialization to be applied, and With yield and purity higher.
Brief description of the drawings
Fig. 1 is the product HPLC collection of illustrative plates of 3- methoxyl group -4- difluoro-methoxy benzaldehyde synthesis steps.
Fig. 2 is the product HPLC collection of illustrative plates of 3- hydroxyl -4- difluoro-methoxy benzaldehyde synthesis steps.
Fig. 3 is the product HPLC collection of illustrative plates of 3- rings the third methoxyl group -4- difluoro-methoxy benzaldehyde synthesis steps.
Fig. 4 is the product HPLC collection of illustrative plates of 3- rings the third methoxyl group -4- difluoro-methoxy-benzoic acid synthesis steps.
Fig. 5 is 3- rings the third methoxyl group -4- difluoro-methoxy-benzoic acids1H-NMR collection of illustrative plates.
Specific embodiment
Further elucidated above is made to the technical scheme in the present invention below with reference to accompanying drawing and specific embodiment.Except another Beyond being described, material, reagent, instrument used in the following example etc. can be obtained by routine business means.
Embodiment 1：The synthesis of 3- rings the third methoxyl group -4- difluoro-methoxy-benzoic acids.
To added in reaction bulb DMF (450mL), vanillic aldehyde (30.0g, 0.2mol) and NaOH (13.0g, 0.325mol), 90 DEG C are warming up to and are stirred 2 hours, then pass to monochlorodifluoromethane gas, TLC detection vanillic aldehyde raw materials disappear Stop heating after mistake.After reaction system is down to room temperature, add water (450mL) that reaction is quenched, then extracted with dichloromethane, organic phase Use saturated sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying that pale yellow oil 3- is obtained after concentration successively Methoxyl group -4- difluoro-methoxies benzaldehyde (31.9g, yield 80%, purity 99.2%, its HPLC collection of illustrative plates is as shown in Figure 1), is not required to Purifying can be directly used for next step reaction.
The product HPLC analysis results of the 3- methoxyl group -4- difluoro-methoxy benzaldehyde synthesis steps of table 1.
To addition DMF (75mL), lithium chloride (1.9g, 0.045mol) and 3- methoxyl group -4- difluoro-methoxies in reaction bulb Benzaldehyde (3.0g, 0.015mol), stirs and is warming up to backflow, and HPLC detection 3- methoxyl group -4- difluoro-methoxies benzaldehydes are former Material stops heating after disappearing.After reaction system is down to room temperature, salt acid for adjusting pH value is added to 1, then be extracted with ethyl acetate, it is organic Saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous sodium sulfate drying, the crude product ethyl acetate after concentration are mutually used successively With n-hexane recrystallization, off-white powder 3- hydroxyl -4- difluoro-methoxies benzaldehydes (0.78g, yield 28%, purity are obtained 97.9%, its HPLC collection of illustrative plates is as shown in Figure 2).
The product HPLC analysis results of the 3- hydroxyl -4- difluoro-methoxy benzaldehyde synthesis steps of table 2.
Chromatographic peak Retention time (min) Peak area Peak area %
1 0.161 2105 0.023
2 1.123 2828 0.031
3 1.493 1365 0.015
4 2.703 1300 0.014
5 3.712 23727 0.261
6 4.864 1362 0.015
7 5.773 9453 0.104
8 6.033 1944 0.021
9 7.848 8904259 97.896
10 10.137 13530 0.149
11 14.172 12473 0.137
12 17.504 121320 1.334
Amount to 9095669 100.000
To addition THF (200mL), potassium carbonate (11.0g, 0.08mol) and 3- hydroxyl -4- difluoromethoxy phenyls in reaction bulb Formaldehyde (10.0g, 0.053mol), adds bromomethyl cyclopropane (10.8g, 0.08mol), TLC detections after being stirred at room temperature 1 hour 3- hydroxyl -4- difluoromethoxy phenyls formaldehyde raw material adds water (100mL) that reaction is quenched after disappearing, then is extracted with dichloromethane, has Machine mutually uses saturated common salt water washing, anhydrous sodium sulfate drying that brown oil 3- ring the third methoxyl group -4- difluoro first is obtained after concentration Epoxide benzaldehyde (10.5g, yield 82%, purity 93.9%, its HPLC collection of illustrative plates is as shown in Figure 3), directly uses by being not required to purifying In next step reaction.
The product HPLC analysis results of 3- rings the third methoxyl group -4- difluoro-methoxy benzaldehyde synthesis steps of table 3.
Chromatographic peak Retention time (min) Peak area Peak area %
1 9.996 5917 0.115
2 11.176 16601 0.323
3 12.020 96465 1.879
4 12.750 11008 0.214
5 13.443 131056 2.553
6 13.849 4819375 93.887
7 14.171 13052 0.254
8 14.603 39673 0.773
Amount to 5133148 100.000
To in reaction bulb add acetic acid (20mL) and 3- rings the third methoxyl group -4- difluoro-methoxies benzaldehyde (5.0g, 0.02mol), sulfamic acid (2.4g, 0.025mol) is added after being stirred at room temperature 0.5 hour, reaction solution adds again after being cooled to 5 DEG C Enter sodium chlorite aqueous solution's (11.2g includes sodium chlorite 2.24g, 0.025mol) of 20wt%, be then warmed to room temperature reaction, TLC detection 3- ring the third methoxyl group -4- difluoromethoxy phenyls formaldehyde raw materials add water (100mL) that reaction is quenched after disappearing, and stirring 1 is small When after filter, filter cake washes with water, obtained after drying white solid 3- ring the third methoxyl group -4- difluoro-methoxy-benzoic acids (4.5g, Yield 85%, purity 98.6%, its HPLC collection of illustrative plates is as shown in Figure 4).Through as shown in Figure 51H-NMR collection of illustrative plates verifies that product is certain It is target product 3- ring the third methoxyl group -4- difluoro-methoxy-benzoic acids.
The product HPLC analysis results of 3- rings the third methoxyl group -4- difluoro-methoxy-benzoic acid synthesis steps of table 4.
Chromatographic peak Retention time (min) Peak area Peak area %
1 8.270 3551 0.266
2 9.579 5768 0.433
3 11.756 1315485 98.681
4 13.076 1947 0.146
5 13.591 6312 0.473
Amount to 1333063 100.000
Embodiment 2：The synthesis of 3- rings the third methoxyl group -4- difluoro-methoxy-benzoic acids.
To added in reaction bulb DMF (450mL), vanillic aldehyde (30.0g, 0.2mol) and potassium hydroxide (18.2g, 0.325mol), 80 DEG C are warming up to and are stirred 2 hours, then pass to monochlorodifluoromethane gas, TLC detection vanillic aldehyde raw materials disappear Stop heating after mistake.After reaction system is down to room temperature, add water (450mL) that reaction is quenched, then extracted with dichloromethane, organic phase Use saturated sodium carbonate solution and saturated common salt water washing, anhydrous sodium sulfate drying that pale yellow oil 3- is obtained after concentration successively Methoxyl group -4- difluoro-methoxies benzaldehyde (30.9g, yield 77.5%, purity 99.4%), is not required to purifying and can be directly used for down Single step reaction.
To addition DMF (75mL), lithium bromide (3.9g, 0.045mol) and 3- methoxyl group -4- difluoro-methoxies in reaction bulb Benzaldehyde (3.0g, 0.015mol), stirs and is warming up to backflow, and HPLC detection 3- methoxyl group -4- difluoro-methoxies benzaldehydes are former Material stops heating after disappearing.After reaction system is down to room temperature, salt acid for adjusting pH value is added to 2, then be extracted with ethyl acetate, it is organic Saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous sodium sulfate drying, the crude product ethyl acetate after concentration are mutually used successively With n-hexane recrystallization, off-white powder 3- hydroxyl -4- difluoro-methoxies benzaldehydes (0.70g, yield 25%, purity are obtained 97.8%).
To addition DCM (200mL), potassium carbonate (11.0g, 0.08mol) and 3- hydroxyl -4- difluoromethoxy phenyls in reaction bulb Formaldehyde (10.0g, 0.053mol), adds bromomethyl cyclopropane (10.8g, 0.08mol), TLC detections after being stirred at room temperature 1 hour 3- hydroxyl -4- difluoromethoxy phenyls formaldehyde raw material adds water (100mL) that reaction is quenched after disappearing, then is extracted with dichloromethane, has Machine mutually uses saturated common salt water washing, anhydrous sodium sulfate drying that brown oil 3- ring the third methoxyl group -4- difluoro first is obtained after concentration Epoxide benzaldehyde (10.2g, yield 80%, purity 93.8%), is not required to purifying and can be directly used for next step reaction.
To in reaction bulb add acetic acid (20mL) and 3- rings the third methoxyl group -4- difluoro-methoxies benzaldehyde (5.0g, 0.02mol), add sulfamic acid (2.4g, 0.025mol) after being stirred at room temperature 0.5 hour, reaction solution be cooled to 10 DEG C after again Sodium chlorite aqueous solution's (15g includes sodium chlorite 2.25g, 0.025mol) of 15wt% is added, reaction is then warmed to room temperature, TLC detection 3- ring the third methoxyl group -4- difluoromethoxy phenyls formaldehyde raw materials add water (100mL) that reaction is quenched after disappearing, and stirring 1 is small When after filter, filter cake washes with water, obtained after drying white solid 3- ring the third methoxyl group -4- difluoro-methoxy-benzoic acids (4.3g, Yield 82%, purity 98.2%).Through1H-NMR collection of illustrative plates verifies that product is target product 3- ring the third methoxyl group -4- difluoro first really P-methoxybenzoic acid.
Embodiment 3：The synthesis of 3- rings the third methoxyl group -4- difluoro-methoxy-benzoic acids.
To addition DMF (450mL), vanillic aldehyde (30.0g, 0.2mol) and potassium carbonate (27.6g, 0.2mol) in reaction bulb, It is warming up to 100 DEG C and stirs 2 hours, then pass to monochlorodifluoromethane gas, TLC detection vanillic aldehyde raw materials stops adding after disappearing Heat.After reaction system is down to room temperature, add water (450mL) that reaction is quenched, then extracted with dichloromethane, organic phase uses saturation successively Sodium carbonate liquor and saturated common salt water washing, anhydrous sodium sulfate drying obtain pale yellow oil 3- methoxyl groups -4- two after concentration Fluorine methoxybenzaldehyde (30.8g, yield 77.3%, purity 99.1%), is not required to purifying and can be directly used for next step reaction.
To addition DMF (75mL), lithium chloride (1.9g, 0.045mol) and 3- methoxyl group -4- difluoro-methoxies in reaction bulb Benzaldehyde (3.0g, 0.015mol), stirs and is warming up to backflow, and HPLC detection 3- methoxyl group -4- difluoro-methoxies benzaldehydes are former Material stops heating after disappearing.After reaction system is down to room temperature, salt acid for adjusting pH value is added to 1.5, then be extracted with ethyl acetate, have Machine mutually uses saturated sodium bicarbonate, water and saturated common salt water washing, anhydrous sodium sulfate drying, the acetic acid second of the crude product after concentration successively Ester and n-hexane are recrystallized, and obtain off-white powder 3- hydroxyl -4- difluoro-methoxies benzaldehydes (0.62g, yield 22%, purity 97.4%).
To addition THF (200mL), potassium carbonate (11.0g, 0.08mol) and 3- hydroxyl -4- difluoromethoxy phenyls in reaction bulb Formaldehyde (10.0g, 0.053mol), adds bromomethyl cyclopropane (10.8g, 0.08mol), TLC detections after being stirred at room temperature 1 hour 3- hydroxyl -4- difluoromethoxy phenyls formaldehyde raw material adds water (100mL) that reaction is quenched after disappearing, then is extracted with dichloromethane, has Machine mutually uses saturated common salt water washing, anhydrous sodium sulfate drying that brown oil 3- ring the third methoxyl group -4- difluoro first is obtained after concentration Epoxide benzaldehyde (10.5g, yield 82%, purity 94.0%), is not required to purifying and can be directly used for next step reaction.
To in reaction bulb add acetic acid (20mL) and 3- rings the third methoxyl group -4- difluoro-methoxies benzaldehyde (5.0g, 0.02mol), sulfamic acid (2.4g, 0.025mol) is added after being stirred at room temperature 0.5 hour, reaction solution adds again after being cooled to 8 DEG C Enter sodium chlorite aqueous solution's (9g includes sodium chlorite 2.25g, 0.025mol) of 25wt%, be then warmed to room temperature reaction, TLC Detection 3- ring the third methoxyl group -4- difluoromethoxy phenyls formaldehyde raw material adds water (100mL) that reaction is quenched after disappearing, and stirs 1 hour After filter, filter cake is washed with water, dry after obtain white solid 3- ring the third methoxyl group -4- difluoro-methoxy-benzoic acids (4.4g, receive Rate 83%, purity 98.1%).Through1H-NMR collection of illustrative plates verifies that product is target product 3- ring the third methoxyl group -4- difluoromethoxies really Yl benzoic acid.

Claims (9)

1. a kind of synthetic method of roflumilast key intermediate, it comprises the following steps：
1) 3- methoxyl group -4- difluoro-methoxy benzaldehydes are prepared：
To the vanillic aldehyde, reaction dissolvent and acid binding agent that are added in reaction vessel as shown in Formula II, under agitation by above-mentioned body System is heated to 80~100 DEG C, then passes to monochlorodifluoromethane, and vanillic aldehyde stops heating, adds water and reaction is quenched after reacting completely Extracted with organic solvent afterwards, organic phase is scrubbed, dry, concentration, obtains the 3- methoxyl group -4- difluoromethoxies as shown in formula III Benzaldehyde；
2) 3- hydroxyl -4- difluoro-methoxy benzaldehydes are prepared：
To adding step 1 in reaction vessel) in the 3- methoxyl group -4- difluoro-methoxies benzaldehyde as shown in formula III, anti-that obtains Solvent and lithium salts are answered, above-mentioned system is heated to backflow under agitation, 3- methoxyl group -4- difluoro-methoxy benzaldehydes are complete Stop heating after reaction, regulation pH value is extracted to after 1~2 with organic solvent, organic phase is scrubbed, drys, concentration, recrystallize, Obtain the 3- hydroxyl -4- difluoro-methoxy benzaldehydes as shown in formula IV；
3) 3- ring the third methoxyl group -4- difluoro-methoxy benzaldehydes are prepared：
To in reaction vessel add step 2) in obtain the 3- hydroxyl -4- difluoro-methoxies benzaldehyde as shown in formula IV, reaction Solvent and acid binding agent, above-mentioned system is stirred at room temperature, and is subsequently adding bromomethyl cyclopropane, 3- hydroxyl -4- difluoromethoxy phenyls Formaldehyde adds water after reacting completely and reaction is quenched, and is then extracted with organic solvent, and organic phase is scrubbed, dry, concentration, obtains such as formula 3- rings the third methoxyl group -4- difluoro-methoxy benzaldehydes shown in V；
4) 3- ring the third methoxyl group -4- difluoro-methoxy-benzoic acids are prepared：
To adding step 3 in reaction vessel) in 3- rings the third methoxyl group -4- difluoro-methoxy benzaldehydes shown as a formula V for obtaining And acetic acid, above-mentioned system is stirred at room temperature, sulfamic acid is subsequently adding, sodium chlorite water is added after being cooled to 5~10 DEG C Solution, is then warmed to room temperature reaction, and 3- rings the third methoxyl group -4- difluoro-methoxy benzaldehydes add water after reacting completely and reaction is quenched, Agitated, filtering, washing, drying, obtain as the third methoxyl group of 3- rings -4- shown in formula I of roflumilast key intermediate Difluoro-methoxy-benzoic acid.
2. synthetic method according to claim 1, it is characterised in that：
Step 1) described in reaction dissolvent be selected from N,N-dimethylformamide, toluene in any one.
3. synthetic method according to claim 1, it is characterised in that：
Step 1) described in acid binding agent be selected from NaOH, potassium hydroxide, potassium carbonate in any one.
4. synthetic method according to claim 1, it is characterised in that：
Step 2) described in reaction dissolvent be selected from N,N-dimethylformamide, toluene in any one.
5. synthetic method according to claim 1, it is characterised in that：
Step 2) described in lithium salts be selected from lithium chloride, lithium bromide in any one.
6. synthetic method according to claim 1, it is characterised in that：
Step 2) described in recrystallize using ethyl acetate/n-hexane, any one in isopropanol/n-hexane.
7. synthetic method according to claim 1, it is characterised in that：
Step 3) described in reaction dissolvent be selected from tetrahydrofuran, dichloromethane in any one.
8. synthetic method according to claim 1, it is characterised in that：
Step 3) described in acid binding agent be selected from potassium carbonate, NaOH, potassium hydroxide in any one.
9. synthetic method according to claim 1, it is characterised in that：
Step 4) described in sodium chlorite aqueous solution the mass percent concentration of sodium chlorite be 15%~25%.
CN201710075456.8A 2017-02-13 2017-02-13 A kind of synthetic method of roflumilast key intermediate Pending CN106883118A (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103214422A (en) * 2013-05-07 2013-07-24 南通大学 Preparation methods and anti-cancer effect of novel substituted amido imidazolone derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103214422A (en) * 2013-05-07 2013-07-24 南通大学 Preparation methods and anti-cancer effect of novel substituted amido imidazolone derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
余磊等: "芳基甲基醚去甲基化反应", 《广东化工》 *

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