CN106831863A - Montelukast sodium intermediate and its preparation method and application - Google Patents
Montelukast sodium intermediate and its preparation method and application Download PDFInfo
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- CN106831863A CN106831863A CN201710044916.0A CN201710044916A CN106831863A CN 106831863 A CN106831863 A CN 106831863A CN 201710044916 A CN201710044916 A CN 201710044916A CN 106831863 A CN106831863 A CN 106831863A
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- 0 Cc(cc1)nc2c1ccc(*)c2 Chemical compound Cc(cc1)nc2c1ccc(*)c2 0.000 description 1
- WQZQFYRSYLXBGP-UHFFFAOYSA-N Cc(cc1)nc2c1ccc(Cl)c2 Chemical compound Cc(cc1)nc2c1ccc(Cl)c2 WQZQFYRSYLXBGP-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
- C07D215/18—Halogen atoms or nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
- C07F9/576—Six-membered rings
- C07F9/60—Quinoline or hydrogenated quinoline ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The present invention relates to a series of noval chemical compounds with below general formula (III) and preparation method thereof.The present invention also relates to formula (III) noval chemical compound Menglusitena synthesis in application.Formula (III) compound is the key intermediate in Menglusitena building-up process, and vital effect, stable chemical nature are served for synthesis final goal compound, preparation process reaction condition is gentle, yield is high, and optical purity is high, is adapted to large-scale production.
Description
Technical field
The invention belongs to pharmaceutical chemistry technical field, and in particular to a kind of Menglusitena key intermediate and its preparation side
Method, further to application of the intermediate in Menglusitena (Montelukast Sodium) synthesis.
Background technology
Menglusitena is the anti-asthmatic medicament developed by United States Merck company, and U.S.'s food was obtained on 2 20th, 1998
The listing approval of product Drug Administration (FDA), trade name2 months 1998 in Finland and Mexico
City, in October, 1998, in U.S.'s list marketing, then lists in succession in the country such as Britain, Canada, Italy, France, Germany.
The LTRA of Menglusitena alternatively property, can and respiratory tract in leukotriene receptor selectivity combination,
The effect of Anaphylactic mediator is competitively blocked, and then blocks the reaction of organ dialogue triolefin, improve respiratory inflammation, make respiratory tract
It is unobstructed, it is a kind of efficient, low toxicity, relieving asthma anti-inflammatory and the Claritin of safety.It is clinically used for childhood asthma and motion causes heavy breathing
The treatment breathed heavily, has broad prospects.
Menglusitena it is chemical entitled：1- [[[(1R) -1- [3- [(1E) -2- (the chloro- 2- quinoline of 7-) vinyl] benzene
Base] -3- [2- (1- hydroxyl -1- Methylethyls) phenyl] propyl group] thio] methyl] cyclopropaneacetic acid sodium, its chemical structural formula is such as
Under：
The patent document of the synthetic method on Menglusitena mainly has CN1046711C in the prior art,
CN1139429A, CN1171873C, CN101321732A, CN105294556A, US20050107612A1,
US20080275243A1, US7417149B2, WO20070572271A1, US20080097104A1, WO2009016191A1,
US7189853B2, WO2005105751A1, WO2005105749A2, WO2008072872A1, WO2007116240A1,
WO2008035086A2 etc..
The current synthetic method on Menglusitena is a lot, and these methods are mainly around chiral carbon and side chain structure C-
The strategy of S keys, can substantially be summarized as following a few classes：
The first kind, first by intermediate 2- (2- (3- (2- (the chloro- 2- quinolyls of 7-)-ethenylphenyl) -3- hydroxypropyls)
Phenyl) chiral alcoholic extract hydroxyl group is converted into leaving group and obtains intermediate 2 in -2- propyl alcohol, then intermediate 2 and parent in the basic conditions
Core reagent 1- thiopurine methyltransferases cyclopropaneacetic acid (or its analog) obtains intermediate 3 by nucleophilic substitution, then by hydrolysis,
Menglusitena target product is obtained into steps such as salt, as shown in synthetic route 1：
Such synthetic method is mainly the alcoholic extract hydroxyl group and methylsufonyl chloride that are connected with chiral carbon reaction generation methanesulfonates
Intermediate 2, but the intermediate is extremely unstable, is susceptible to the side reactions such as elimination, intramolecular cyclization.On the other hand such reaction
Must be carried out in a low temperature of about -30 DEG C, and require that product is stored in about -15 DEG C, condition is harsh, be unfavorable for industrial big raw
Produce.Mention being reacted by intermediate 1 and thionyl chloride in patent US20080275243A1 and alcoholic extract hydroxyl group is switched into chloro thing, the party
The ee values only 64% of method gained intermediate 2 can just obtain satisfactory target product, it is necessary to split crystallization, and overall yield is notable
Reduce, cost is significantly improved, while producing a large amount of useless enantiomer accessory substances.
Hanmi Science Co., Ltd. patent document CN101558042B, CN101808998B and Shanghai Di Sainuo chemical pharmacies
Disclosed in Co., Ltd patent application document CN105294556A use chlorine phosphate diphenyl ester as electrophilic reagent with it is chiral
The method that alcoholic extract hydroxyl group reaction prepares montelukast intermediate, it is specific as follows：
In this reaction scheme, in the basic conditions, the tertiary alcohol is easy to attack and diphenyl phosphate as necleophilic reaction site
Connected chiral carbon, it is more to be susceptible to intramolecular cyclization, side reaction, is unfavorable for purifying products, reduces reaction yield, increased
Financial cost.
Equations of The Second Kind, is reacted after obtaining intermediate 2 by intermediate 1, and thioacetic acid or the reaction of its sylvite obtain intermediate
4, intermediate 4 is taken off in being condensed to yield with 2- (1- (bromomethyl) cyclopropyl) methyl acetate (or its analog) after acetyl group is protected
Mesosome 3, then Menglusitena target product is obtained by hydrolysis, into steps such as salt, as shown in synthetic route 2：
Also there is use (E) -2- [3- [3- [2- (the chloro- 2- quinolyls of 7-) vinyl] phenyl] -3- oxopropyls] benzoic acid
Methyl esters is initiation material, first obtains the analog 4 ' of intermediate 4, then obtains intermediate with methyl-magnesium-bromide RMgBr addition
4, then obtain intermediate 3 with 2- (1- (bromomethyl) cyclopropyl) methyl acetate.
For above-mentioned Equations of The Second Kind synthesis strategy, the unstable problem of mesylate intermediate 2 is equally existed；On the other hand,
Ethanethioyl is introduced, reactions steps is increased and then is reduced economy；While key starting material 2- (1- (bromomethyl) rings
Propyl group) methyl acetate in the market there is no that producer provides, the synthesis strategy is not suitable for industrialized production.
In sum, the preparation method generally existing of Menglusitena intermediated chemistry property shakiness in the prior art
Determine, be susceptible to the side reactions such as elimination, intramolecular cyclization, severe reaction conditions are unfavorable for industrialized production, anti-asthmatic medicament Meng
The preparing technical field of montelukast sodium is, it is necessary to develop a kind of more ripe, excellent in stability process route.
The content of the invention
The invention provides the compound with formula (III) formula, the preparation method of formula (III) compound is additionally provided.
Invention further provides the method that one kind prepares Menglusitena as key intermediate using formula (III) compound.
Concrete scheme of the invention is as follows：
The invention discloses formula (III) compound：
Wherein, X represents methyl, C1-6Alkoxy, phenoxy group, benzyloxy；
R1Represent C1-6Alkyl, phenyl, benzyl；
R2Represent C1-6Alkyl, phenyl, benzyl.
C mentioned above1-6Alkyl refers to the 1-6 straight or branched alkyl of carbon atom.For example：Methyl, ethyl,
Propyl group, isopropyl, butyl, isobutyl group, the tert-butyl group, sec-butyl, amyl group, neopentyl, hexyl etc..
C mentioned above1-6Alkoxy refers to 1~6 straight or branched alkoxyl of carbon atom.For example：Methoxy
Base, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, amoxy, neopentyl oxygen,
Hexyloxy etc..It is preferred that having 1~4 straight or branched alkoxyl of carbon atom, particularly preferred methoxy or ethoxy.Most preferably
Methoxyl group.
It is preferred that R1Represent phenyl；
It is preferred that R2Represent phenyl；
It is preferred that X represents methyl or C1-4Alkoxy；
Particularly preferred X represents methyl, methoxy or ethoxy；
Preferred compounds of the invention is selected from：
The invention provides a kind of preparation method of formula (III) compound, specific route is as follows：
By formula (IV) compound and formula (IVA) compound dissolves in organic solvent, be condensed in the presence of alkali respectively
To formula (III) compound.
Reaction temperature is 0~100 DEG C, preferably 20~50 DEG C；
Reaction time is 1~5h, preferably 2-3h；
The alkali be selected from sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N, N- diisopropylethylamine, 1,
Carbon -7- the alkene of 8- diazabicylos [5,4,0] 11, DMAP, pyridine, imidazoles, sodium hydride, NaOH, hydrogen-oxygen
Change potassium, cesium hydroxide, calcium hydroxide, sodium acid carbonate, sodium carbonate, potassium carbonate, cesium carbonate, one or more in calcium oxide；Formula
(IV) compound and the mol ratio of the alkali are 1：(1~5), preferably 1：(2~3)；
Formula (IV) compound and formula (IVA) compound mol ratio be 1：(1~5), preferably 1：(1~2).
Present invention also offers the method that one kind prepares Menglusitena as reaction intermediate using formula (III) compound,
Comprise the following steps：
(1) 1- thiopurine methyltransferases cyclopropaneacetic acid or its salt are added sequentially in organic solvent with alkali, are subsequently adding formula (III)
Compound, formula (II) compound is obtained in 20~60 DEG C of stirring reactions；Reaction time 2-4h；
(2) Lewis acid activation agent is added in organic solvent, then under -10~5 DEG C of temperature conditionss, adds first
Base RMgBr, stirs 0~1h, then formula (II) compound solution is added into Lewis acid activation agent-methyl Grignard reaction
In liquid, Montelukast acid is prepared by addition reaction, and formula (I) compound, i.e. Meng Lusi are obtained further across into salt refining
Special sodium.
Alkali described in above step (1) is selected from sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, triethylamine, N, N-
Diisopropylethylamine, the carbon -7- alkene of 1,8- diazabicylos [5,4,0] 11, DMAP, pyridine, imidazoles, hydrogenation
In sodium, NaOH, potassium hydroxide, cesium hydroxide, calcium hydroxide, sodium acid carbonate, sodium carbonate, potassium carbonate, cesium carbonate, calcium oxide
One or more；Formula (III) compound is 1 with the mol ratio of the alkali：(1~5), preferably 1：(2~4)；
Above step (1) Chinese style (III) compound is 1 with the mol ratio of 1- thiopurine methyltransferases cyclopropaneacetic acid or salt：(1~5),
Preferably 1：(2~3)；
Preferably, the above step (1) includes following operation：1- thiopurine methyltransferase cyclopropaneacetic acids are dissolved in two
In methyl sulfoxide, under nitrogen atmosphere, methanol solution of sodium methylate is added, stir 0.5h, formula (III) compound is then dissolved in two
In first sulfoxide, and add into above-mentioned reaction system, in 20~60 DEG C of 2~4h of stirring reaction, question response uses 1mol/L after finishing
Watery hydrochloric acid reaction is quenched, extract, collect organic phase, be concentrated under reduced pressure, dry, obtain formula (II) compound；
Further,
Lewis acid activation agent described in above step (2) is selected from cerous chloride, zinc chloride, lithium chloride, cobalt chloride, chlorination
One or more in lanthanum, chromium chloride；It is preferred that cerous chloride.
Methyl grignard reagent described in above step (2) is selected from methyl-magnesium-chloride, methyl-magnesium-bromide or methylpyridinium iodide magnesium
One kind, preferred methyl-magnesium-chloride；Formula (II) compound is 1 with the mol ratio of the methyl grignard reagent：(3~10), preferably
It is 1：(4~6)；
Above step (2) Chinese style (II) compound is 1 with the mol ratio of Lewis acid activation agent：(0~2), preferably 1：
(1~1.5)；
Preferably, the above step (2) includes following operation：Cerous chloride is added in tetrahydrofuran,
50~80 DEG C are warming up to, 1h is stirred, -10~5 DEG C are cooled to, under -10~5 DEG C of temperature conditionss, methyl-magnesium-chloride tetrahydrochysene is added
Tetrahydrofuran solution, stirs 0.5~1h, then by the tetrahydrofuran solution of formula (II) compound in reaction system is added to, by addition
Reaction prepares Montelukast acid, and obtains formula (I) compound i.e. MK further across into salt refining.
Unless otherwise indicated, the following term in claims and specification has following implication：
In the present inventionThe site that expression chemically reacts；
In the present invention, " LG " represents leaving group, such as OMs, OTs, Cl, Br, I, phosphate；
In the present invention, term " compound " not only includes the compound in itself, also including its pharmaceutically acceptable salt
Or its solvate.
New key intermediate the invention provides MK and preparation method thereof, while providing a synthesis
The new technology route of MK.The stable chemical nature of the key intermediate, for prepare during Menglusitena can gram
Take in existing syntheti c route using the tertiary alcohol as necleophilic reaction site, it is easy to the chiral carbon that attack is connected with leaving group, Yi Fa
Raw intramolecular cyclization, the shortcoming more than side reaction, and whole course of reaction mild condition, chiral carbonoid will not be sent out in course of reaction
Changing, optical purity is high, it is easy to purify, and is suitable for industrialized large-scaled production.
Specific embodiment
The present invention is further illustrated below by embodiment, for a person skilled in the art, should not be by under
Row embodiment is interpreted as limitation of the present invention, according to the teaching of prior art, it is changed or is improved belong to it is of the invention
In protection domain.
Embodiment 1：The synthesis of a of intermediate III
The a compounds (50g, 109.2mmol) of formula IV are dissolved in 500mL dichloromethane, addition triethylamine (22.1g,
218.4mmol), diphenyl phosphate chloride (44g, 163.8mmol) is added dropwise, after completion of dropping, 3h, TLC inspections is stirred at rising to 30 DEG C
Survey raw material reaction complete.Reaction solution is poured into the watery hydrochloric acid of 500mL 1mol/L, extract and separate organic phase uses saturated carbon successively
Sour hydrogen sodium solution and brine It simultaneously collect organic phase, through drying, decolourize after be concentrated under reduced pressure, obtain final product 74.5g oily formulas
III a compounds, yield is 99%.MS:690[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40 (d, J=8.8Hz, 1H), 8.04 (d, J=1.6Hz,
1H), 8.02-7.99 (d, J=8.8Hz, 1H), 7.93-7.91 (d, J=8.8Hz, 1H), 7.90-7.86 (d, J=16.4Hz,
1H), 7.82 (s, 1H), 7.80-7.78 (d, J=7.2Hz, 1H), 7.75-7.73 (d, J=6.8Hz, 1H), 7.61-7.59
(dd, J=8.4Hz, 1.6Hz, 1H), 7.51-7.50 (d, J=16.4Hz, 1H), 7.47-7.10 (m, 15H), 5.75-5.70
(m, 1H), 3.76 (s, 3H), 3.03-2.96 (td, J=12.8Hz, 4.8Hz, 1H), 2.86-2.78 ((td, J=12.8Hz,
4.8Hz,1H),2.37-2.36(m,1H),2.34-2.33(m,1H)
Embodiment 2：The synthesis of the b of intermediate III
The b compounds (50g, 105.9mmol) of formula IV are dissolved in 500mL ethyl acetate, addition triethylamine (32.1g,
317.7mmol), diphenyl phosphate chloride (56.9g, 211.8mmol) is added dropwise, after completion of dropping, 2h, TLC is stirred at rising to 50 DEG C
Detection raw material reaction is complete.Reaction solution is poured into the watery hydrochloric acid of 500mL 1mol/L, extract and separate organic phase, uses full successively
With sodium bicarbonate solution and brine It and collect organic phase, through drying, decolourize after be concentrated under reduced pressure, obtain final product 72.3g oil
The b compounds of shape formula III, yield is 97%.MS:704[M+H]
Embodiment 3：The synthesis of the c of intermediate III
The b compounds (30g, 63.6mmol) of formula IV are dissolved in 300mL toluene, 0 DEG C is cooled to, N, N- diisopropyls is added
Ethamine (41.1g, 317.8mmol), is added dropwise diethyl chloro-phosphate (54.8g, 317.8mmol), after completion of dropping, rises to 100 DEG C
Lower stirring 1h, TLC detection raw material reaction are complete.Reaction solution is poured into the watery hydrochloric acid of 300mL 1mol/L, 300mL second is added
Acetoacetic ester is extracted, and organic phase with saturated sodium bicarbonate solution and brine It and collects organic phase successively, by drying, is decolourized
After be concentrated under reduced pressure, obtain final product the c compounds of 38g oilies formula III, yield is 98%.MS:608[M+H]
Embodiment 4：The synthesis of the d of intermediate III
The d compounds (40g, 82.3mmol) of formula IV are dissolved in 400mL tetrahydrofurans, 0 DEG C is cooled to, 4- diformazan ammonia is added
Yl pyridines (10.1g, 82.3mmol), are added dropwise diisopropyl chlorophosphate (16.5g, 82.3mmol), after completion of dropping, are kept for 0 DEG C
Lower stirring 5h, TLC detection raw material fundamental reaction finish rear terminating reaction.Reaction solution is poured into the watery hydrochloric acid of 400mL1mol/L
In, 400mL ethyl acetate is added, organic phase uses saturated sodium bicarbonate solution and brine It successively, collects organic phase, through dry
It is dry, decolourize and be concentrated under reduced pressure, obtain final product the d compounds of 50g oilies formula III, yield is 93.5%.MS:650 [M+H] embodiments 5：
The synthesis of the e of intermediate III
The e compounds (10g, 22.6mmol) of formula IV are dissolved in 100mL acetonitriles, addition NaOH (2.712g,
67.8mmol), diphenyl phosphate chloride (18.2g, 67.8mmol) is added dropwise, after completion of dropping, 2.5h, TLC is stirred at rising to 40 DEG C
Detection raw material reaction is finished, terminating reaction.Reaction solution is poured into the watery hydrochloric acid of 100mL 1mol/L, 100mL acetic acid is added
Ethyl ester extract and separate organic phase, successively with saturated sodium bicarbonate solution and brine It, collects organic phase, through drying, decolourizes
After be concentrated under reduced pressure, obtain final product the e compounds of 15g oilies formula III, yield is 98.7%.MS:674[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.42-8.40 (d, J=8.8Hz, 1H), 8.04 (d, J=1.6Hz,
1H), 8.02-7.99 (d, J=8.8Hz, 1H), 7.93-7.91 (d, J=8.8Hz, 1H), 7.90-7.86 (d, J=16.4Hz,
1H), 7.82 (s, 1H), 7.80-7.78 (d, J=7.2Hz, 1H), 7.75-7.73 (d, J=6.8Hz, 1H), 7.61-7.59
(dd, J=8.4Hz, 1.6Hz, 1H), 7.51-7.50 (d, J=16.4Hz, 1H), 7.47-7.10 (m, 15H), 5.75-5.70
(m,1H),2.91-2.84(m,1H),2.76-2.69(m,1H),2.53(s,3H),2.34-2.31(m,1H),2.36-2.28
(m,1H)
Embodiment 6：The synthesis of the f of intermediate III
The f compounds (10g, 19.2mmol) of formula IV are dissolved in 100mL 2- butanone, addition potassium hydroxide (2.2g,
38.4mmol), diphenyl phosphate chloride (10.3g, 38.4mmol) is added dropwise, after completion of dropping, 3h, TLC inspections is stirred at rising to 30 DEG C
Survey raw material reaction to finish, terminating reaction.Reaction solution is poured into the watery hydrochloric acid of 100mL 1mol/L, 100mL acetic acid second is added
Ester is extracted, and organic phase uses saturated sodium bicarbonate solution and brine It successively, collects organic phase, is carried out after drying, decolouring
It is concentrated under reduced pressure, the f compounds of 15g oilies formula III are obtained final product, yield is 98.7%.
MS:752[M+H]
Embodiment 7：The synthesis of intermediate II a
1- thiopurine methyltransferases cyclopropaneacetic acid (16g, 109.5mmol) are dissolved in 160mL dimethyl sulfoxides, nitrogen protective condition
Under, at 20 DEG C or so, the methanol solution (37.5g, 208.1mmol) of 30wt% sodium methoxides is added dropwise, finish, room temperature reaction 0.5h,
In being dissolved in III a compounds (37.8g, 54.8mmol) in 380ml dimethyl sulfoxides and add to reaction system, after be warming up to 30 DEG C and stir
Mix reaction 3h, TLC detection raw material reaction and finish rear terminating reaction.Reaction solution is added to the cold dilute hydrochloric acid of 300mL 1mol/L
In, 0 DEG C of temperature control separates out solid, and be dissolved in filter cake in ethyl acetate, saturated common salt water washing 2 times, collect by suction filtration, filter cake washing
Organic phase, is concentrated under reduced pressure after drying, decolouring, obtains final product a compounds of 35.8g yellowish-brown oilies formula II.By yellowish-brown oily
The a compounds of formula II are dissolved in 215mL ethyl acetate, under nitrogen protection, dicyclohexyl amine (27.7g, 152.7mmol) are added dropwise, and are finished,
5h is stirred at room temperature, a small amount of solid is separated out, 430mL n-hexanes are slowly added dropwise, finishes, 12h is stirred at room temperature, suction filtration, filter cake uses 1:1
Ethyl acetate/n-hexane mixed solvent washing, 50 DEG C of dryings obtain the dicyclohexyl amine salt 41.2g of a compounds of formula II, and yield is
97.7%.MS:586[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:8.48-8.46 (d, J=8.4Hz, 1H), 8.36 (brs, 1H), 8.05
(s, 1H), 8.05-8.03 (d, J=8Hz, 1H), 8.01-7.99 (d, J=8.8Hz, 1H), 7.96-7.92 (s, J=16Hz,
1H), 7.76-7.74 (d, J=7.2Hz, 1H), 7.70 (s, 1H), 7.65-7.17 (m, 7H), 3.93 (t, 1H), 3.76 (s,
3H),2.94(m,1H),2.80(m,1H),2.30(m,2H),2.11(m,2H),1.98(m,2H),0.39(m,4H)
Embodiment 8：The synthesis of intermediate II b
1- thiopurine methyltransferase cyclopropaneacetic acids sodium (12.5g, 74.4mmol) is dissolved in 125mL dimethylformamides, nitrogen is protected
Potassium tert-butoxide (12.7g, 113.6mmol) is added at 20 DEG C or so under the conditions of shield, afterwards room temperature reaction 0.5h, by the b chemical combination of formula III
Thing (20g, 28.4mmol) is dissolved in 200ml dimethylformamides and adds into reaction system, is warming up to 60 DEG C of reactions 2h, TLC
Detection raw material reaction finishes rear terminating reaction.Reaction solution is added into the cold dilute hydrochloric acid of 200mL1mol/L, 0 DEG C of temperature control, separated out
Be dissolved in filter cake in ethyl acetate by solid, suction filtration, filter cake washing, and saturated aqueous common salt is washed twice, and collects organic phase, is dried, and is taken off
Color, is concentrated under reduced pressure, and obtains final product the b compounds of 22g yellowish-brown oilies formula II.By the grease by embodiment 7 into two hexamethylenes
The method of amine salt obtains the dicyclohexyl amine salt 21.1g of the b compounds of formula II, and yield is 95%.MS:600[M+H]
Embodiment 9：The synthesis of intermediate II b
1- thiopurine methyltransferase cyclopropaneacetic acids potassium (30.3g, 164.5mmol) is dissolved in 300mL dimethylformamides, nitrogen is protected
Shield, at 20 DEG C or so, adds potassium tert-butoxide (18.4g, 164.5mmol), finishes, room temperature reaction 0.5h, by III c compounds
During (20g, 32.9mmol) is dissolved in 200ml dimethylformamides and adds to reaction system, 2h, TLC detection raw materials are reacted at 20 DEG C
Terminating reaction after completion of the reaction.Reaction solution is added into the cold dilute hydrochloric acid of 200mL1mol/L, 0 DEG C of temperature control, separate out solid, taken out
Filter, filter cake washing, filter cake is dissolved in ethyl acetate, and saturated aqueous common salt is washed twice, and collects organic phase, is dried, and is decolourized, and is carried out
It is concentrated under reduced pressure, obtain final product the b compounds of 23g yellowish-brown oilies formula II.By the grease by the side into dicyclohexyl amine salt in embodiment 7
Method obtains the dicyclohexyl amine salt 23.6g of the b compounds of formula II, and yield is 92%.
Embodiment 10：The synthesis of intermediate II d
1- thiopurine methyltransferase cyclopropaneacetic acids lithium (2.4g, 15.4mmol) is dissolved in 25mL ethyl acetate, nitrogen protection, 20
DEG C or so, 1,8- diazabicylos [5,4,0] 11 carbon -7- alkene (2.3g, 15.4mmol) is added, finish, room temperature reaction 0.5h,
In being dissolved in the d compounds (10g, 15.4mmol) of formula III in 100mL ethyl acetate and drop to reaction solution, finish, be warming up to 40
DEG C reaction 4h, TLC detection raw material fundamental reaction finish rear terminating reaction.Reaction solution is added to cold dilute salt of 100mL 1mol/L
In acid, 0 DEG C of temperature control separates out solid, and be dissolved in filter cake in ethyl acetate, saturated common salt water washing 2 times, receive by suction filtration, filter cake washing
Collection organic phase, dries, and decolourizes, and is concentrated under reduced pressure, and obtains final product the d compounds of 10g yellowish-brown oilies formula II.By the grease by implementation
The method into dicyclohexyl amine salt in example 7 obtains the dicyclohexyl amine salt 10.9g of the d compounds of formula II, and yield is 90%.MS:614[M
+H]
Embodiment 11：The synthesis of intermediate II e
1- thiopurine methyltransferases cyclopropaneacetic acid (9.8g, 66.9mmol) are dissolved in 100mL acetonitriles, nitrogen protection, on 20 DEG C of left sides
The right side, adds potassium hydroxide (3.8g, 66.9mmol), finishes, room temperature reaction 0.5h, by the e compounds (15g, 22.3mmol) of formula III
It is dissolved in 150mL acetonitriles and drops in reaction solution, finish, is warming up to 30 DEG C of reaction 3h, TLC detection raw material reactions and finishes, eventually
Only react.By in the cold dilute hydrochloric acid of reaction solution addition 150mL 1mol/L, 0 DEG C of temperature control separates out solid, and suction filtration, filter cake is washed, will
Filter cake is dissolved in ethyl acetate, saturated common salt water washing 2 times, collects organic phase, is dried, and is decolourized, and is concentrated under reduced pressure, and is obtained final product
The e compounds of 16.6g yellowish-brown oilies formula II.The grease is obtained into the e of formula II by the method into dicyclohexyl amine salt in embodiment 7
The dicyclohexyl amine salt 15.4g of compound, yield is 92%.MS:570[M+H]
1H-NMR(400MHz,DMSO-d6),ppm:12.03 (s, 1H), 8.48-8.46 (d, J=8.4Hz, 1H), 8.02-
7.25(m,14H),3.93(t,1H),3.76(s,3H),2.84(m,1H),2.68(m,1H),2.52(s,3H),2.30(s,
2H),2.11(s,2H),2.05(s,2H),0.36(m,4H)
Embodiment 12：The synthesis of intermediate II f
1- thiopurine methyltransferases cyclopropaneacetic acid (3.9g, 26.6mmol) are dissolved in 100mL acetonitriles, nitrogen protection, on 20 DEG C of left sides
The right side, add 60wt% sodium hydride (1.1g, 26.6mmol), finish, room temperature reaction 0.5h, by the f compounds of formula III (10g,
13.3mmol) it is dissolved in 150mL acetonitriles and drops in reaction solution, finish, is warming up to 50 DEG C of reaction 2h, TLC detection raw materials anti-
Should finish, terminating reaction.Reaction solution is added into the cold dilute hydrochloric acid of 100mL 1mol/L, 0 DEG C of temperature control, precipitation solid, suction filtration,
Filter cake is washed, and filter cake is dissolved in ethyl acetate, saturated common salt water washing 2 times, collects organic phase, is dried, and is decolourized, and is depressurized
Concentration, obtains final product the f compounds of 12g yellowish-brown oilies formula II.The grease is obtained by the method into dicyclohexyl amine salt in embodiment 7
To the dicyclohexyl amine salt 9.9g of Formula II f compounds, yield is 90%.MS:648[M+H]
Embodiment 13：The preparation of Menglusitena
Step 1：The preparation of montelukast acid
Cerous chloride (4.2g, 17.1mmol) is suspended in 100mL tetrahydrofurans, nitrogen protection is warming up to 65 DEG C and stirs
1h is mixed, -5 DEG C are cooled to, 22.8mL methyl-magnesium-chlorides tetrahydrofuran solution (68.4mmol, 3mol/L) are added dropwise, finished, stirred
1h, in being dissolved in a compounds (10g, 17.1mmol) of formula II in 100mL tetrahydrofurans and drop to reaction solution, finishes, and keeps 0
DEG C reaction 1.5h.TLC detection raw material reactions are finished, terminating reaction.During reaction solution added into the cold dilute hydrochloric acid of 100mL 1mol/L,
Dichloromethane is extracted, saturated common salt water washing 2 times, collects organic phase, is dried, and is decolourized, and is concentrated under reduced pressure, and obtains final product 9.8g yellow
Oily Formulas I ' compound montelukast acid, yield is 98%.MS:584[M-H]
Step 2：The preparation of Menglusitena
By Formulas I ' compound (9.8g, 16.7mmol) is dissolved in 60mL methyl alcohol, and the first of NaOH is slowly added dropwise at room temperature
Alcoholic solution, when the pH value of reaction solution is 9~10, stops being added dropwise, and after stirring 30min, decompression boils off solvent, and residue is dissolved in
30mL toluene, is then slowly added dropwise 100mL normal heptanes, and 4h is stirred after completion of dropping, filtering, and solid vacuum at 50~60 DEG C is done
Dry 12h, obtains final product Menglusitena 9.6g, and yield is 95%.
Embodiment 14：The preparation of Menglusitena
Step 1：The preparation of montelukast acid
55.7mL methyl-magnesium-bromides toluene solution (167mmol, 3mol/L) are added to 100mL toluene, -10 are cooled to
DEG C, then the b compounds (10g, 16.7mmol) of formula II are dissolved in 100mL toluene, under nitrogen protection, in dropping to reaction solution,
Finish, keep -5 DEG C of reaction 5h.TLC detection raw material reactions are finished, terminating reaction.By the cold of reaction solution addition 100mL 1mol/L
In watery hydrochloric acid, dichloromethane extraction, saturated common salt water washing 2 times collects organic phase, dries, and decolourizes, and is concentrated under reduced pressure, i.e.,
Obtain 8.3g yellow oilies Formulas I ' compound montelukast acid, yield is 85%.
Step 2：The preparation of Menglusitena
By Formulas I ' compound prepares 7.8g Menglusitenas by the method into sodium salt in embodiment 13, and yield is
90%.
Embodiment 15：The preparation of Menglusitena
Step 1：The preparation of montelukast acid
Zinc chloride (4.4g, 32.6mmol) is suspended in 100mL tetrahydrofurans, under nitrogen atmosphere with 5 DEG C of temperature strips
Under part, 16.3mL methyl-magnesium-chlorides tetrahydrofuran solution (48.9mmol, 3mol/L) are added dropwise and continue to stir 40min afterwards, by the d of formula II
During compound (10g, 16.3mmol) is dissolved in 100mL tetrahydrofurans and drops to reaction system, continue after completion of dropping anti-
Answer 4h.Terminating reaction after being finished through TLC detections raw material fundamental reaction.Reaction solution is added to the cold dilute hydrochloric acid of 100mL 1mol/L
In, dichloromethane extraction, saturated common salt water washing 2 times collects organic phase, is concentrated under reduced pressure after drying, decolouring, obtains final product
8.8g yellow oilies Formulas I ' compound montelukast acid, yield is 92%.
Step 2：The preparation of Menglusitena
By Formulas I ' compound prepares 8.4g Menglusitenas by the method into sodium salt in embodiment 13, and yield is
92%.
Embodiment 16：The preparation of Menglusitena
Step 1：The preparation of montelukast acid
Lithium chloride (1.1g, 26.3mmol) is suspended in 100mL tetrahydrofurans, under the conditions of -10 DEG C, 35mL first is added dropwise
Base magnesium bromide tetrahydrofuran solution (105mmol, 3mol/L) simultaneously stirs 0.5h, and the e compounds (10g, 17.5mmol) of formula II is molten
In the 100mL tetrahydrofurans and reaction system is dropped to, react 5h.Terminating reaction after being finished through TLC detection raw material reactions.Will
Reaction solution is added in the cold dilute hydrochloric acid of 100mL1mol/L, and dichloromethane extraction, saturated common salt water washing 2 times collects organic phase,
It is concentrated under reduced pressure after drying, decolouring, is obtained final product 9.2g yellow oilies Formulas I ' compound montelukast acid, yield is 90%.MS:
584[M-H]
Step 2：The preparation of Menglusitena
By Formulas I ' compound prepares 8.8g Menglusitenas by the method into sodium salt in embodiment 8, and yield is
92%.
Embodiment 17：The preparation of Menglusitena
Step 1：The preparation of montelukast acid
Lanthanum chloride (3.6g, 15.4mmol) and lithium chloride (0.65g, 15.4mmol) are suspended in 100mL toluene, room temperature
Stirring 1h, is cooled to 0 DEG C, and nitrogen protection is added dropwise 20.5mL methylpyridinium iodide magnesium tetrahydrofuran solution (61.6mmol, 3mol/L),
Finish, stir 1h, in being dissolved in the f compounds (10g, 15.4mmol) of formula II in 100mL tetrahydrofurans and drop to reaction solution, plus
Finish, keep 0 DEG C of reaction 3h.TLC detection raw material reactions are finished, terminating reaction.Reaction solution is added cold dilute salt of 100mL1mol/L
In acid, dichloromethane extraction, saturated common salt water washing 2 times collects organic phase, dries, and decolourizes, and is concentrated under reduced pressure, and obtains final product
8.5g yellow oilies Formulas I ' compound montelukast acid, yield is 94%.
Step 2：The preparation of Menglusitena
By Formulas I ' compound prepares 7.9g Menglusitenas by the method into sodium salt in embodiment 8, and yield is
90%.
Claims (10)
1. the compound and its pharmaceutically acceptable salt or solvate shown in a kind of formula (III)：
Wherein：
X represents methyl, C1-6Alkoxy, phenoxy group, benzyloxy；
R1Represent C1-6Alkyl, phenyl, benzyl；
R2Represent C1-6Alkyl, phenyl, benzyl.
2. the compound and its pharmaceutically acceptable salt or solvate shown in formula (III) according to claim 1,
Wherein X represents methyl, methoxy or ethoxy；R1、R2Represent phenyl.
3. compound and its pharmaceutically acceptable salt or solvent shown in formula (III) described in a kind of claim 1 or 2
The preparation method of compound, the method includes：By formula (IV) compound and formula (IVA) compound is dissolved in organic solvent, in alkali
In the presence of reaction obtain formula (III) compound；
Synthetic route is as follows：
。
4. compound and its pharmaceutically acceptable salt shown in formula (III) according to claim 3 or solvate
Preparation method, it is characterised in that：The alkali is selected from triethylamine, N, N- diisopropylethylamine, the carbon -7- of 1,8- diazabicylos 11
Alkene, DMAP, pyridine, imidazoles, NaH, NaOH, KOH, Ca (OH)2、NaHCO3、Na2CO3、K2CO3、CsCO3、CsOH
Or one or more in CaO；Formula (IV) compound is 1 with the mol ratio of the alkali：(1~5)；Formula (IV) chemical combination
Thing and formula (IVA) compound mol ratio be 1：(1~5).
5. compound and its pharmaceutically acceptable salt shown in formula (III) according to claim 3 or solvate
Preparation method, it is characterised in that：Reaction temperature is 0~100 DEG C, and the reaction time is 1~5h.
6. a kind of synthetic method of Menglusitena, it is characterised in that with shown in the formula (III) described in claim 1 or 2
Compound as intermediate, method and step is：
(1) in 1- thiopurine methyltransferases cyclopropaneacetic acid or its salt and alkali being sequentially added into organic solvent, formula (III) compound is subsequently adding,
In 20~60 DEG C of 2~4h of stirring reaction, formula (II) compound is obtained；
(2) Lewis acid activation agent is added in organic solvent, then under -10~5 DEG C of temperature conditionss, adds methyl Grignard
Reagent, stir 0~1h, then formula (II) compound solution added into Lewis acid activation agent-methyl Grignard reaction solution, instead
1.5~5h is answered, Montelukast acid is prepared by addition reaction, and MK is obtained further across into salt refining.
。
7. the synthetic method of Menglusitena according to claim 6, it is characterised in that alkali is selected from described in step (1)
Triethylamine, N, N- diisopropylethylamine, the carbon -7- alkene of 1,8- diazabicylos 11, DMAP, pyridine, imidazoles,
NaH、NaOH、KOH、Ca(OH)2、NaHCO3、Na2CO3、K2CO3、CsCO3, one or more in CsOH or CaO；Formula (III) is changed
Compound is 1 with the mol ratio of the alkali：(1~5).
8. the synthetic method of Menglusitena according to claim 6, it is characterised in that the Louis described in step (2)
This acid activators is selected from one or more in cerous chloride, zinc chloride, lithium chloride, cobalt chloride, lanthanum chloride, chromium chloride.
9. the synthetic method of Menglusitena according to claim 6, it is characterised in that：Formula described in step (2)
(II) compound and the mol ratio of Lewis acid activation agent are 1：(0~2).
10. the synthetic method of Menglusitena according to claim 6, it is characterised in that：Methyl lattice described in step (2)
Family name's reagent is methyl-magnesium-chloride, methyl-magnesium-bromide or methylpyridinium iodide magnesium；Formula (II) compound rubs with methyl Grignard
You are than being 1：(3~10).
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| WO2018133533A1 (en) * | 2017-01-20 | 2018-07-26 | 山东百诺医药股份有限公司 | Montelukast sodium intermediate, preparation method and application thereof |
| CN111892535A (en) * | 2020-08-27 | 2020-11-06 | 鲁南制药集团股份有限公司 | Synthesis method of montelukast sodium |
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| US20050107612A1 (en) * | 2002-12-30 | 2005-05-19 | Dr. Reddy's Laboratories Limited | Process for preparation of montelukast and its salts |
| CN101558042A (en) * | 2006-12-14 | 2009-10-14 | 韩美药品株式会社 | Method of preparing montelukast and intermediates used therein |
| WO2012123506A1 (en) * | 2011-03-15 | 2012-09-20 | Laboratorios Lesvi, S.L. | Montelukast intermediate camphorsulfonic salt |
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| CN106831863B (en) * | 2017-01-20 | 2018-09-21 | 山东百诺医药股份有限公司 | Montelukast sodium intermediate and its preparation method and application |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050107612A1 (en) * | 2002-12-30 | 2005-05-19 | Dr. Reddy's Laboratories Limited | Process for preparation of montelukast and its salts |
| CN101558042A (en) * | 2006-12-14 | 2009-10-14 | 韩美药品株式会社 | Method of preparing montelukast and intermediates used therein |
| WO2012123506A1 (en) * | 2011-03-15 | 2012-09-20 | Laboratorios Lesvi, S.L. | Montelukast intermediate camphorsulfonic salt |
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|---|---|---|---|---|
| WO2018133533A1 (en) * | 2017-01-20 | 2018-07-26 | 山东百诺医药股份有限公司 | Montelukast sodium intermediate, preparation method and application thereof |
| CN111892535A (en) * | 2020-08-27 | 2020-11-06 | 鲁南制药集团股份有限公司 | Synthesis method of montelukast sodium |
| CN111892535B (en) * | 2020-08-27 | 2023-04-11 | 鲁南制药集团股份有限公司 | Synthesis method of montelukast sodium |
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