CN102617339A - 3-cyclopropylmethoxy-4-halogen benzoic acid or derivative and application thereof - Google Patents
3-cyclopropylmethoxy-4-halogen benzoic acid or derivative and application thereof Download PDFInfo
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Abstract
The invention discloses 3-cyclopropylmethoxy-4-halogen benzoic acid or a derivative (I) and an application thereof. The 3-cyclopropylmethoxy-4-halogen benzoic acid or the derivative (I) can be used for preparing roflumilast and has the advantages that raw materials are easy to obtain, the reaction condition is mild, the operation is simple and convenient, complicated postprocessing processes such as column chromatography, high-temperature rectification and the like are avoided. 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (IV) prepared by a compound (I) is subjected to a condensation reaction to obtain the roflumilast, intermediates in each step and goal products are high in purity, the quality is stable and controllable, the preparation cost of the roflumilast is greatly reduced, and the 3-cyclopropylmethoxy-4-halogen benzoic acid or the derivative (I) is suitable for industrialization large-scale preparation. A general molecular formula of the compound (I) is shown as follows.
Description
Technical field
The present invention relates to the key intermediate of synthetic roflumilast, specifically, relate to 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof.
Background technology
(Roflumilast Daxas) by the exploitation of Switzerland Nycomed company, obtains European Union's approval listing in June, 2010 and is used for serious chronic obstructive pulmonary disease (COPD) and chronic bronchitis roflumilast.And obtain drugs approved by FDA in February, 2011 and be used to treat serious chronic obstructive pulmonary disease (COPD), commodity are called Daliresp.Roflumilast is a kind of oral selectivity phosphodiesterase 4 (PDE4) suppressor factor; This medicine is verified can be the new class COPD medicine that obtains European Union's approval during the last ten years first with a kind of brand-new mode of action treatment chronic obstructive pulmonary disease (COPD).Roflumilast is the oral tablet of 1 medication on the one, is applicable to the treatment of keeping of the relevant serious COPD of the adult patient chronic bronchitis that frequently increases the weight of medical history.
Roflumilast (Roflumilast)
At present, the midbody of disclosed synthetic roflumilast comprises both at home and abroad:
(1) disclose the key intermediate 3-cyclo propyl methoxy-4-methyl hydroxybenzoate of synthetic roflumilast among the WO2005026095 (patent families EP1670742), this compound is through 3, and the 4-methyl dihydroxy benzoate prepares through alkylation.
(2) patent WO2008006509 (patent families US2008015226; EP2044023 and CN101490004) in disclose through 3-hydroxyl-difluoro-methoxy phenyl aldehyde midbody and prepared a kind of method of roflumilast; Key intermediate is by 3, and the 4-Dihydroxy benzaldehyde obtains through the alkylation preparation.
(3) (patent families US6822116, the midbody 3-that EP1554248) discloses another kind of preparation roflumilast encircles third methoxyl group-4-hydroxyl bromobenzene to WO2004033430.This key intermediate is to be set out by pyrocatechol to prepare through alkylation, bromination.
(4) CN201010603095 discloses other a kind of midbody 3-hydroxyl-4-difluoro-methoxy-benzoic acid methyl esters for preparing roflumilast.It is to be set out by 3-nitro-4-methyl hydroxybenzoate, through alkylation, reduction, the diazotization hydrolysis prepares again.
Wherein, Through 3-cyclo propyl methoxy-4-methyl hydroxybenzoate and 3-hydroxyl-difluoro-methoxy phenyl aldehyde key intermediate as the preparation roflumilast; Alkylated reaction poor selectivity when preparing these midbodys need be carried out purifying through column chromatography, is not suitable for industrialization and prepares in a large number.Encircle the method for third methoxyl group-4-hydroxyl bromobenzene intermediate preparation roflumilast through 3-and need use low-temp reaction and hypertoxic CO gas, the processing condition harshness also is difficult to satisfy industrial needs.
Summary of the invention
The object of the invention is to provide a kind of 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof, to overcome the above-mentioned defective that prior art exists;
Another object of the present invention is the application that discloses described 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof.
Described 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof, for having the compound shown in the formula (I):
Wherein:
X represents chlorine, iodine or bromine;
R represents COOH, COOM, COOR
1, CONH
2, CONHR
1, CONR
1R
2, CONR
3Or CN;
R
1, R
2Represent C1-C6 alkyl, benzyl or substituted benzyl;
NR
3Represent nitrogenous or nitrogenous and five yuan or hexa-member heterocycle oxygen;
M representative: Li, Na, K, Mg or Ca;
Substituted benzyl is C1-C4 alkyl benzyl, C1-C4 alkoxybenzyl, halogeno-benzyl or nitrobenzyl.
Preferably, X is iodine or bromine;
Preferably, R is COOH, COOM, COOR
1Or CONH
2Or CN;
Preferably, the alkyl of said C1-C6 is methyl, ethyl, propyl group, sec.-propyl, butyl or cyclopropyl methyl;
Preferably, said NR
3Heterocycle is Pyrrolidine, piperidines or morpholine;
Preferably, the C1-C4 alkyl benzyl is to methyl-benzyl or to Ethylbenzyl;
Preferably, the C1-C4 alkoxybenzyl is to methoxy-benzyl or to ethoxy benzyl;
Preferably, said halogeno-benzyl is a p-chlorobenzyl or to bromobenzyl;
Preferably, nitrobenzyl is to nitrobenzyl;
Wherein:
When X represents chlorine or iodine;
R represents COOH, COOM, COOR
1, CONH
2, CONHR
1, CONR
3Or CN;
When X represents bromine;
R represents COOM, CONH
2, CONHR
1, CON (R
1)
2, CONR
3Or CN;
R
1, R
2Represent C1-C6 alkyl, benzyl or substituted benzyl;
NR
3Represent nitrogenous or nitrogenous and five yuan or hexa-member heterocycle oxygen;
M representative: Li, Na, K, Mg or Ca;
Substituted benzyl is C1-C4 alkyl benzyl, C1-C4 alkoxybenzyl, halogeno-benzyl or nitrobenzyl;
Preferably, R is COOH, COOM, COOR
1Or CONH
2Or CN;
Preferably, the C1-C6 alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl or cyclopropyl methyl;
Preferably, NR
3Heterocycle is Pyrrolidine, piperidines or morpholine;
Preferably, the C1-C4 alkyl benzyl is to methyl-benzyl or to Ethylbenzyl;
Preferably, the C1-C4 alkoxybenzyl is to methoxy-benzyl or to ethoxy benzyl;
Preferably, halogeno-benzyl is a p-chlorobenzyl or to bromobenzyl;
Preferably, nitrobenzyl is to nitrobenzyl;
Preferably, described 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof comprises:
I-1 3-cyclo propyl methoxy-4-iodobenzoic acid,
I-2 3-cyclo propyl methoxy-4-iodobenzoic acid sodium,
I-3 3-cyclo propyl methoxy-4-iodobenzoic acid methyl esters,
I-4 3-cyclo propyl methoxy-4-iodobenzoic acid ethyl ester,
I-5 3-cyclo propyl methoxy-4-iodobenzoic acid benzyl ester,
I-6 3-cyclo propyl methoxy-4-phenyl-iodide methane amide,
I-7 3-cyclo propyl methoxy-4-iodo cyanic acid benzene,
I-8 3-cyclo propyl methoxy-4-bromobenzene sodium formiate,
I-9 3-cyclo propyl methoxy-4-bromobenzene methane amide,
I-10 3-cyclo propyl methoxy-4-bromo cyanic acid benzene,
I-11 (3-cyclo propyl methoxy-4-iodine substituted phenyl)-piperidines ketone or
I-12 (3-cyclo propyl methoxy-4-iodine substituted phenyl)-morpholine ketone;
The structural formula of above-claimed cpd is seen table 1.
The chemical structure of table 1. compound (I)
Wherein, be more preferably:
I-1 3-cyclo propyl methoxy-4-iodobenzoic acid,
I-3 3-cyclo propyl methoxy-4-iodobenzoic acid methyl esters,
I-4 3-cyclo propyl methoxy-4-iodobenzoic acid ethyl ester,
I-5 3-cyclo propyl methoxy-4-iodobenzoic acid benzyl ester or
I-6 3-cyclo propyl methoxy-4-phenyl-iodide methane amide;
The compound method of said 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof (I) is following:
Wherein:
When X represents chlorine or iodine;
R represents COOH, COOM, COOR
1, CONH
2, CONHR
1, CONR
3Or CN;
When X represents bromine;
R represents COOM, CONH
2, CONHR
1, CON (R
1)
2, CONR
3Or CN;
R
1, R
2Represent C1-C6 alkyl, benzyl or substituted benzyl;
NR
3Represent nitrogenous or nitrogenous and five yuan or hexa-member heterocycle oxygen;
M representative: Li, Na, K, Mg or Ca;
Substituted benzyl is C1-C4 alkyl benzyl, C1-C4 alkoxybenzyl, halogeno-benzyl or nitrobenzyl.
In the presence of alkali, obtain 3-by 3-hydroxyl-4-halogenated benzoic acid or derivatives thereof (II) and encircle third methoxyl group-4-halogenated benzoic acid or derivatives thereof (I) with the compound reaction of the ring third methylating reagent formula (VIII).Encircle the compound that third methylating reagent is formula (VIII), wherein Y is a leavings group, like Cl, Br, OMs (mesyloxy) or OTs (tolysulfonyl oxygen base).The ring third used solvent that methylates is selected from one or more of acetone, ETHYLE ACETATE, DMF (N, dinethylformamide), DMSO (DMSO 99.8MIN.), NMP (N-Methyl pyrrolidone), THF, dioxane, toluene, acetonitrile; Preferred solvent is one or more in DMF, DMSO, NMP, dioxane, the toluene; Preferred solvent is DMF, dioxane or toluene.The ring third used alkali that methylates is selected from sodium hydroxide, Pottasium Hydroxide, Lithium Hydroxide MonoHydrate, sodium ethylate, sodium methylate, potassium tert.-butoxide, sodium hydride, yellow soda ash, salt of wormwood or cesium carbonate; Preferred alkali is sodium hydroxide, Pottasium Hydroxide, salt of wormwood or cesium carbonate, and preferred alkali is sodium hydroxide or salt of wormwood.Preferred temperature of reaction is 20-100 ℃, and preferred temperature is 60-90 ℃; The preferred reaction times is 1-15 hour, and the preferred reaction times is 3-8 hour.
The compound of formula (II) can be purchased, also can from 3-hydroxy-benzoic acid and analogue thereof (Synthesis 2002,17,2503; Helvetica Chimica Acta.1989,72,594; J.Med.Chem.2003,46,1845.) or 3-hydroxyl-4-nitrobenzoic acid and analogue thereof through synthetic (Bioorganic and Medicinal Chemistry, 2009,17,6567 of obtaining of simple method; Journal of Medicinal Chemistry, 2009,52,2289.)
Compound shown in (I) provided by the invention can be used for synthetic roflumilast (V), and the application method and the route of preparation roflumilast are following:
Wherein:
When X represents chlorine or iodine;
R represents COOH, COOM, COOR
1, CONH
2, CONHR
1, CONR
3Or CN;
When X represents bromine;
R represents COOM, CONH
2, CONHR
1, CON (R
1)
2, CONR
3Or CN;
R
1, R
2Represent C1-C6 alkyl, benzyl or substituted benzyl;
NR
3Represent nitrogenous or nitrogenous and five yuan or hexa-member heterocycle oxygen;
M representative: Li, Na, K, Mg or Ca;
Substituted benzyl is C1-C4 alkyl benzyl, C1-C4 alkoxybenzyl, halogeno-benzyl or nitrobenzyl.
In this synthetic route, be raw material with compound (I):
When R is COOH, COOM, COOR
1The time, in basic soln, hydroxylation obtains 3-cyclo propyl methoxy-4-hydroxy-benzoic acid (III) under the metal catalyst effect.Under the alkali effect, obtain formula (IV) compound through alkylation then with difluoromethyl reagent.Last with 3,5-two chloro-4-amido-pyridine condensation prepared obtain roflumilast (V).
When R is CONH
2, CONHR
1, CON (R
1)
2, during CN, in basic soln, hydroxylation obtains formula (VI) compound under the metal catalyst effect.Under the alkali effect, obtain formula (VII) compound through alkylation then with difluoromethyl reagent.Method through hydrolysis transforms 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid (IV), and last with 3,5-two chloro-4-amido-pyridine condensations obtain roflumilast.
Preparation roflumilast midbody of the present invention " 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof (I) "; Different fully with the chemical structure of roflumilast midbody in present publication and the bibliographical information; Have tangible novel structure property, adopt midbody disclosed by the invention to carry out in the building-up process of roflumilast, avoided the use and the column chromatography purification of expensive metal catalyzer; Significantly reduced the preparation cost of roflumilast, suitable industrialization prepares in a large number.Therefore; Adopt 3-cyclo propyl methoxy disclosed by the invention-4-halogenated benzoic acid or derivatives thereof (I); In the process of preparation roflumilast key intermediate 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid (IV); Overcome document and reported preparing method's defective and deficiency, had tangible creativeness, possessed bigger positive progressive effect and actual application value.
Adopt roflumilast midbody 3-cyclo propyl methoxy disclosed by the invention-4-halogenated benzoic acid or derivatives thereof (I), the preparation roflumilast has following characteristics:
Raw material is easy to get, reaction conditions gentle, and is easy and simple to handle, and reaction yield is high; Be adapted to suitability for industrialized production, avoid complicated last handling processes such as column chromatography and high temperature rectifying, significantly reduced preparation cost; Midbody (III) process alkylated reaction or midbody (VII) are through hydrolysis reaction, and recrystallizing and refining gets compound (IV), again through condensation; Refining roflumilast, each goes on foot midbody and title product purity is high, and is stable and controllable for quality.
Disclosed roflumilast midbody and application thereof in this patent have overcome defective and deficiency that document has been reported the roflumilast preparation method, have bigger positive progressive effect and actual application value.
Embodiment
Logical method one:
(0.15-0.25mol and alkylation solvent 150mL are 60-80 ℃ of stirring 2-5 hour down with the compound (0.1mol) of formula (II), alkali (0.2-0.3mol), ring third methylating reagent (VIII).Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain formula (I) compound, productive rate 70-99%.
Embodiment 1
3-cyclo propyl methoxy-4-iodo-benzoic acid (I-1)
According to logical method one described method, with 3-hydroxyl-4-iodo-benzoic acid methyl esters (27.8g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (20.1g 0.15mol) with DMF 150mL, stirred 2 hours down at 80 ℃ the brooethyl Trimetylene.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodo-benzoic acid methyl esters (I-3) bullion.Gained bullion reflux 4 hours in 10% sodium hydrate methanol solution (150mL).Reduce to room temperature, remove solvent under reduced pressure, add water (100mL), the hydrochloric acid modulation pH=2 with 5mol/L filters and obtains white solid 3-cyclo propyl methoxy-4-iodo-benzoic acid (I-1) 30.1g, productive rate 95%.
1H?NMR(CDCl
3)：δ0.42-0.47(m，2H)，0.64-0.70(m，2H)，1.24-1.45(m，1H)，3.98(d，2H)，7.36(d，1H)，7.45(s，1H)，7.87(d，1H)。
Embodiment 2
3-cyclo propyl methoxy-4-iodo-benzoic acid sodium (I-2)
According to logical method one described method, with 3-hydroxyl-4-iodo-benzoic acid methyl esters (27.8g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (20.1g 0.15mol) with NMP 150mL, stirred 2 hours down at 80 ℃ the brooethyl Trimetylene.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodo-benzoic acid methyl esters (I-3) bullion.Gained bullion reflux 4 hours in 10% sodium hydrate methanol solution (100mL).Reduce to room temperature, filter and obtain white solid 3-cyclo propyl methoxy-4-iodo-benzoic acid sodium (I-2) 23.7g, productive rate 70%
1H?NMR(CD
3OD)：δ0.45-0.49(m，2H)，0.66-0.73(m，2H)，1.27-1.47(m，1H)，3.95(d，2H)，7.31(d，1H)，7.41(s，1H)，7.88(d，1H)。
Embodiment 3
3-cyclo propyl methoxy-4-iodo-benzoic acid methyl esters (I-3)
According to logical method one described method, with 3-hydroxyl-4-iodo-benzoic acid methyl esters (27.8g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (20.1g 0.15mol) with DMSO 150mL, stirred 2 hours down at 80 ℃ the brooethyl Trimetylene.Reaction is used ethyl acetate extraction after diluting with 450g water, and organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodo-benzoic acid methyl esters (I-3) 33.1g, productive rate 99%.
1H?NMR(CDCl
3)：δ0.42-0.48(m，2H)，0.64-0.71(m，2H)，1.25-1.45(m，1H)，3.93(s，3H)，3.98(d，2H)，7.38(d，1H)，7.42(s，1H)，7.87(d，1H)。
Embodiment 4
3-cyclo propyl methoxy-4-iodo ethyl benzoate (I-4)
According to logical method one described method, with 3-hydroxyl-4-iodo ethyl benzoate (29.2g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (18.1g 0.2mol) with DMF 150mL, stirred 5 hours down at 80 ℃ the chloromethyl Trimetylene.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodo ethyl benzoate (I-4) 34.5g, productive rate 99%.
1H?NMR(CDCl
3)：δ0.42-0.48(m，2H)，0.64-0.71(m，2H)，1.25-1.45(m，4H)，3.93(q，2H)，3.98(d，2H)，7.37(d，1H)，7.41(s，1H)，7.88(d，1H)。
Embodiment 5
3-cyclo propyl methoxy-4-iodo-benzoic acid benzyl ester (I-5)
According to logical method one described method, with 3-hydroxyl-4-iodo-benzoic acid benzyl ester (35.3g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (18.1g, 0.2mol) with 1,4-dioxane 150mL stirred 5 hours down at 80 ℃ the chloromethyl Trimetylene.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodo-benzoic acid benzyl ester (I-5) 40.0g productive rate 99%.
1H?NMR(CDCl
3)：δ0.42-0.48(m，2H)，0.64-0.71(m，2H)，1.25-1.45(m，1H)，3.98(d，2H)，5.07(s，2H)，7.25-7.37(m，6H)，7.41(s，1H)，7.88(d，1H)。
Embodiment 6
3-cyclo propyl methoxy-4-iodobenzene methane amide (I-6)
According to logical method one described method, with 3-hydroxyl-4-iodo-benzoic acid methyl esters (27.8g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (20.1g 0.15mol) with DMF 150mL, stirred 2 hours down at 80 ℃ the brooethyl Trimetylene.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodo-benzoic acid methyl esters (I-3) bullion.Gained bullion, saturated ammonia methanol solution (100mL) 50 are spent stirred overnight.Cold filtration obtains white solid 3-cyclo propyl methoxy-4-iodobenzene methane amide (I-6) 22.2g, productive rate 70%.
1H?NMR(CD
3OD)：δ0.42-0.48(m，2H)，0.65-0.73(m，2H)，1.25-1.47(m，1H)，3.97(d，2H)，7.32(d，1H)，7.43(s，1H)，7.88(d，1H)。
Embodiment 7
3-cyclo propyl methoxy-4-iodine cyanic acid benzene (I-7)
According to logical method one described method, with 3-hydroxyl-4-iodine cyanic acid benzene (24.5g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (45.2g 0.2mol) with DMSO 150mL, stirred 3 hours down at 80 ℃ Trimetylene methyl p-toluenesulfonic esters.Reaction is used ethyl acetate extraction after diluting with 450g water, and organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodine cyanic acid benzene (I-7), productive rate 99%.
1H?NMR(CDCl
3)：δ0.42-0.48(m，2H)，0.64-0.71(m，2H)，1.25-1.45(1，4H)，3.98(d，2H)，7.31(d，1H)，7.45(s，1H)，7.85(d，1H)。
Embodiment 8
3-cyclo propyl methoxy-4-bromo-benzoic acid sodium (I-8)
According to logical method one described method, with 3-hydroxyl-4-methyl-bromobenzoate (23.0g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (20.1g 0.15mol) with DMF 150mL, stirred 2 hours down at 80 ℃ the brooethyl Trimetylene.Reaction is used ethyl acetate extraction after diluting with 450g water, and organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-methyl-bromobenzoate (I-3) bullion.Gained bullion reflux 4 hours in 10% sodium hydrate methanol solution (100mL).Reduce to room temperature, filter and obtain white solid 3-cyclo propyl methoxy-4-bromo-benzoic acid sodium (I-8) 21.0g, productive rate 72%
1H?NMR(CD
3OD)：δ0.45-0.49(m，2H)，0.66-0.73(m，2H)，1.27-1.47(m，1H)，3.95(d，2H)，7.32(d，1H)，7.42(s，1H)，7.89(d，1H)。
Embodiment 9
3-cyclo propyl methoxy-4-brombenzamide (I-9)
According to logical method one described method, with 3-hydroxyl-4-methyl-bromobenzoate (23.0g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (20.1g 0.15mol) with DMSO 150mL, stirred 2 hours down at 80 ℃ the brooethyl Trimetylene.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-methyl-bromobenzoate bullion.Gained bullion, saturated ammonia methanol solution (100mL) 50 are spent stirred overnight.Cold filtration obtains white solid 3-cyclo propyl methoxy-4-brombenzamide (I-9) 19.6g, productive rate 73%.
1H?NMR(CD
3OD)：δ0.42-0.47(m，2H)，0.65-0.73(m，2H)，1.25-1.47(m，1H)，3.97(d，2H)，7.31(d，1H)，7.42(s，1H)，7.85(d，1H)。
Embodiment 10
3-cyclo propyl methoxy-4-bromine cyanic acid benzene (I-10)
According to logical method one described method, with 3-hydroxyl-4-bromine cyanic acid benzene (19.7g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (45.2g 0.2mol) with DMSO 150mL, stirred 3 hours down at 80 ℃ Trimetylene methyl p-toluenesulfonic esters.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-bromine cyanic acid benzene (I-10) 25.1g, productive rate 99%.
1H?NMR(CDCl
3)：δ0.42-0.48(m，2H)，0.64-0.71(m，2H)，1.25-1.45(1，4H)，3.97(d，2H)，7.32(d，1H)，7.46(s，1H)，7.88(d，1H)。
Embodiment 11
(3-cyclo propyl methoxy-4-iodine substituted phenyl)-piperidines ketone (I-11)
According to logical method one described method, with 3-hydroxyl-4-iodo-benzoic acid methyl esters (27.8g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (20.1g 0.15mol) with DMF 150mL, stirred 2 hours down at 80 ℃ the brooethyl Trimetylene.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodo-benzoic acid methyl esters (I-3) bullion.Gained bullion reflux 4 hours in 10% sodium hydrate methanol solution (150mL).Reduce to room temperature, remove solvent under reduced pressure, add water (100mL), the hydrochloric acid modulation pH=2 with 5mol/L filters and obtains white solid 3-cyclo propyl methoxy-4-iodo-benzoic acid (I-1).With compound (I-1) piperidines (8.6g, 0.1mol), HATU (38.8g, 0.1mol) 50 the degree stirred overnight.Filtration obtains (3-cyclo propyl methoxy-4-iodine substituted phenyl)-piperidines ketone (I-11) 35.2g, productive rate 90%.
1H?NMR(CD
3OD)：δ0.42-0.49(m，2H)，0.66-0.73(m，2H)，1.25-1.47(m，1H)，1.52-1.75(m，5H)，3.53-3.76(m，4H)，3.97(d，2H)，7.32(d，1H)，7.473(s，1H)，7.78(d，1H)。
Embodiment 12
(3-cyclo propyl methoxy-4-iodine substituted phenyl)-morpholine ketone (I-12)
According to logical method one described method, with 3-hydroxyl-4-iodo-benzoic acid methyl esters (27.8g, 0.1mol), salt of wormwood (27.6g, 0.2mol), (20.1g 0.15mol) with DMF 150mL, stirred 2 hours down at 80 ℃ the brooethyl Trimetylene.Behind the reaction dilute with water, use ethyl acetate extraction, organic layer is told in washing, washing, drying.Remove solvent under reduced pressure, obtain 3-cyclo propyl methoxy-4-iodo-benzoic acid methyl esters (I-3) bullion.Gained bullion reflux 4 hours in 10% sodium hydrate methanol solution (150mL).Reduce to room temperature, remove solvent under reduced pressure, add water (100mL), the hydrochloric acid modulation pH=2 with 5mol/L filters and obtains white solid 3-cyclo propyl methoxy-4-iodo-benzoic acid (I-1).With compound (I-1) morpholine (8.8g, 0.1mol), HATU (38.8g, 0.1mol) 50 the degree stirred overnight.Filtration obtains (3-cyclo propyl methoxy-4-iodine substituted phenyl)-morpholine ketone (I-12) 34.9g, productive rate 88%.
1H?NMR(CD
3OD)：δ0.42-0.48(m，2H)，0.65-0.73(m，2H)，1.25-1.47(m，1H)，3.42-3.67(m，4H)，3.87-3.99(m，6H)，7.31(d，1H)，7.47(s，1H)，7.79(d，1H)。
Embodiment 13
Roflumilast (V)
Step 1: with cuprous iodide (1.9g, 0.01mol), the 8-pyridone (2.9g, 0.02mol), DMSO 100mL and the 3-cyclo propyl methoxy-(32.9g 0.1mol) joins in the reactor drum 4-iodo-benzoic acid methyl esters (I-3).Under the restir, add 25% potassium hydroxide aqueous solution 100mL.Be heated to 100 ℃ of reactions 24 hours, be cooled to room temperature and filter away copper catalyst.Be adjusted to acidity with hydrochloric acid, ethyl acetate extraction, anhydrous sodium sulfate drying, remove solvent under reduced pressure after, obtain 3-cyclo propyl methoxy-4-hydroxy-benzoic acid (III) 19.6g, yield 95%.
1H?NMR(CDCl
3)：δ0.37-0.40(m，2H)，0.62-0.77(m，2H)，1.23-1.40(m，1H)，3.97(d，2H)，7.00(d，1H)，7.63(s，1H)，7.75(d，1H)，12.1(br，1H)。
Step 2: with salt of wormwood (41.4g; 0.30mol) join and contain in the DMF 200mL reactor drum, be warming up to 80 ℃, under vigorous stirring, drip 3-cyclo propyl methoxy-4-hydroxy-benzoic acid (III) (20.8g; 0.10mol) and 1-chloro-1; (45.7g, DMF 100mL solution 0.30mol) finish reaction 2 hours to 1-difluoroacetic acid sodium.Cool to 50 ℃, add 10% sodium hydroxide 200mL aqueous solution dilution after, heated and stirred 2 hours.Reduce to that the Hydrogen chloride with 500mL transfers to acidity after the room temperature, water layer is used ethyl acetate extraction, anhydrous sodium sulfate drying, remove solvent under reduced pressure after, recrystallization obtains 3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid (IV) 20.1g, yield 81%.
1H?NMR(CDCl
3)：δ0.39-0.42(m，2H)，0.70-0.73(m，2H)，1.30-1.39(m，1H)，3.97(d，2H)，6.77(t，1H)，7.26(d，1H)，7.69(s，1H)，7.75(d，1H)。
Step 3:3-cyclo propyl methoxy-4-difluoro-methoxy-benzoic acid (IV) (25.8g, toluene 0.1mol) (150mL) solution is heated to backflow, and the adding sulfur oxychloride (17.8g, 0.15mol), refluxing and stirring reaction 0.5 hour, it is for use that distillation is concentrated into 75mL.(12.0g 0.105mol) joins 3 under 90 ℃, (17.9g in toluene 0.11mol) (150mL) solution, refluxing and stirring half a hour is added dropwise to ready made acyl chlorides toluene liquation to 5-two chloro-4-amido-pyridines, and refluxing and stirring 2 hours with potassium tert.-butoxide.After reducing to 80 ℃, successively add the hydrochloric acid soln 50mL washing of saturated sodium bicarbonate solution 50mL, aqueous solution 50mL and 2mol/L.After dividing water-yielding stratum, after organic layer was cooled to room temperature, crystallization filtered and obtains white solid roflumilast (V) 30.2g, productive rate 75%.
1H?NMR(DMSO-d
6)：δ0.35-0.420(m，2H)，0.65-0.75(m，2H)，1.21-1.39(m，1H)，3.99(d，2H)，7.25(t，1H)，7.37(d，1H)，7.66(d，1H)，7.71(s，1H)，8.79(s，2H)，10.68(s，1H)。
Claims (9)
1.3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof is characterized in that, for having the compound shown in the formula (I):
Wherein:
X represents chlorine, iodine or bromine;
R represents COOH, COOM, COOR
1, CONH
2, CONHR
1, CONR
1R
2, CONR
3Or CN;
R
1, R
2Represent C1-C6 alkyl, benzyl or substituted benzyl;
NR
3Represent nitrogenous or nitrogenous and five yuan or hexa-member heterocycle oxygen;
M representative: Li, Na, K, Mg or Ca;
Substituted benzyl is C1-C4 alkyl benzyl, C1-C4 alkoxybenzyl, halogeno-benzyl or nitrobenzyl.
2. 3-cyclo propyl methoxy according to claim 1-4-halogenated benzoic acid or derivatives thereof is characterized in that, the C1-C6 alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl or cyclopropyl methyl.
3. 3-cyclo propyl methoxy according to claim 1 and 2-4-halogenated benzoic acid or derivatives thereof is characterized in that X is iodine or bromine.
4. 3-cyclo propyl methoxy according to claim 1 and 2-4-halogenated benzoic acid or derivatives thereof is characterized in that R is COOH, COOM, COOR
1Or CONH
2Or CN.
5. 3-cyclo propyl methoxy according to claim 3-4-halogenated benzoic acid or derivatives thereof is characterized in that R is COOH, COOM, COOR
1Or CONH
2Or CN.
6.3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof is characterized in that, for having the compound shown in the formula (I):
Wherein:
When X represents chlorine or iodine;
R represents COOH, COOM, COOR
1, CONH
2, CONHR
1, CONR
3Or CN;
When X represents bromine;
R represents COOM, CONH
2, CONHR
1, CON (R
1)
2, CONR
3Or CN;
R
1, R
2Represent C1-C6 alkyl, benzyl or substituted benzyl;
NR
3Represent nitrogenous or nitrogenous and five yuan or hexa-member heterocycle oxygen;
M representative: Li, Na, K, Mg or Ca;
Substituted benzyl is C1-C4 alkyl benzyl, C1-C4 alkoxybenzyl, halogeno-benzyl or nitrobenzyl.
7. 3-cyclo propyl methoxy according to claim 6-4-halogenated benzoic acid or derivatives thereof is characterized in that, the C1-C6 alkyl is methyl, ethyl, propyl group, sec.-propyl, butyl or cyclopropyl methyl.
8.3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof is characterized in that, comprising:
I-1 3-cyclo propyl methoxy-4-iodobenzoic acid,
I-2 3-cyclo propyl methoxy-4-iodobenzoic acid sodium,
I-3 3-cyclo propyl methoxy-4-iodobenzoic acid methyl esters,
I-4 3-cyclo propyl methoxy-4-iodobenzoic acid ethyl ester,
I-5 3-cyclo propyl methoxy-4-iodobenzoic acid benzyl ester,
I-6 3-cyclo propyl methoxy-4-phenyl-iodide methane amide,
I-7 3-cyclo propyl methoxy-4-iodo cyanic acid benzene,
I-8 3-cyclo propyl methoxy-4-bromobenzene sodium formiate,
I-9 3-cyclo propyl methoxy-4-bromobenzene methane amide,
I-10 3-cyclo propyl methoxy-4-bromo cyanic acid benzene,
I-11 (3-cyclo propyl methoxy-4-iodine substituted phenyl)-piperidines ketone or
I-12 (3-cyclo propyl methoxy-4-iodine substituted phenyl)-morpholine ketone.
9. the application of each described 3-cyclo propyl methoxy-4-halogenated benzoic acid or derivatives thereof of claim 1～8 is characterized in that, is used for synthetic roflumilast.
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