CN106966976A - A kind of preparation method of Methylbenzoquate - Google Patents
A kind of preparation method of Methylbenzoquate Download PDFInfo
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- CN106966976A CN106966976A CN201710211667.XA CN201710211667A CN106966976A CN 106966976 A CN106966976 A CN 106966976A CN 201710211667 A CN201710211667 A CN 201710211667A CN 106966976 A CN106966976 A CN 106966976A
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- butyl
- methylbenzoquate
- benzyloxy
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- NNOPDLNHPOLRRE-UHFFFAOYSA-N Nequinate Chemical compound CCCCC1=CC(C(C(C(=O)OC)=CN2)=O)=C2C=C1OCC1=CC=CC=C1 NNOPDLNHPOLRRE-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 63
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 57
- 238000003756 stirring Methods 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 25
- 238000010792 warming Methods 0.000 claims description 22
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- 239000012043 crude product Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 13
- 235000019441 ethanol Nutrition 0.000 claims description 10
- 239000007787 solid Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 7
- 238000001556 precipitation Methods 0.000 claims description 6
- FZBHVMVKTREEEM-UHFFFAOYSA-N 4-butyl-3-phenylmethoxyaniline Chemical class CCCCC1=CC=C(N)C=C1OCC1=CC=CC=C1 FZBHVMVKTREEEM-UHFFFAOYSA-N 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- 238000004821 distillation Methods 0.000 claims description 5
- 238000001953 recrystallisation Methods 0.000 claims description 5
- DQWPFSLDHJDLRL-UHFFFAOYSA-N triethyl phosphate Chemical compound CCOP(=O)(OCC)OCC DQWPFSLDHJDLRL-UHFFFAOYSA-N 0.000 claims description 5
- 238000005292 vacuum distillation Methods 0.000 claims description 5
- YSMRWXYRXBRSND-UHFFFAOYSA-N TOTP Chemical compound CC1=CC=CC=C1OP(=O)(OC=1C(=CC=CC=1)C)OC1=CC=CC=C1C YSMRWXYRXBRSND-UHFFFAOYSA-N 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 9
- 238000000034 method Methods 0.000 abstract description 7
- 230000001165 anti-coccidial effect Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000002253 acid Substances 0.000 abstract description 2
- 230000032050 esterification Effects 0.000 abstract description 2
- 238000005886 esterification reaction Methods 0.000 abstract description 2
- -1 methoxy methylenes Chemical class 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 1
- 125000004093 cyano group Chemical group *C#N 0.000 abstract 1
- CTTOYDHUFQNBDZ-UHFFFAOYSA-N ethyl 2-methoxyprop-2-enoate Chemical compound CCOC(=O)C(=C)OC CTTOYDHUFQNBDZ-UHFFFAOYSA-N 0.000 abstract 1
- KUVIRDUPAGKTER-UHFFFAOYSA-N n-phenylmethoxyaniline Chemical compound C=1C=CC=CC=1CONC1=CC=CC=C1 KUVIRDUPAGKTER-UHFFFAOYSA-N 0.000 abstract 1
- 238000006467 substitution reaction Methods 0.000 abstract 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 15
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 4
- 229920001651 Cyanoacrylate Polymers 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000000273 veterinary drug Substances 0.000 description 3
- WOJCNFFUQQHXGX-UHFFFAOYSA-N 2-(propan-2-yloxymethylidene)propanedioic acid Chemical compound CC(C)OC=C(C(O)=O)C(O)=O WOJCNFFUQQHXGX-UHFFFAOYSA-N 0.000 description 2
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000003224 coccidiostatic agent Substances 0.000 description 2
- JHAYEQICABJSTP-UHFFFAOYSA-N decoquinate Chemical compound N1C=C(C(=O)OCC)C(=O)C2=C1C=C(OCC)C(OCCCCCCCCCC)=C2 JHAYEQICABJSTP-UHFFFAOYSA-N 0.000 description 2
- JMANVNJQNLATNU-UHFFFAOYSA-N glycolonitrile Natural products N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 2
- 230000008676 import Effects 0.000 description 2
- 229960003540 oxyquinoline Drugs 0.000 description 2
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 2
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 2
- RQQDJYROSYLPPK-UHFFFAOYSA-N N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 Chemical class N1=CC=CC2=CC=CC=C21.N1=CC=CC2=CC=CC=C21 RQQDJYROSYLPPK-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960001878 decoquinate Drugs 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
Classifications
-
- 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
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Abstract
A kind of preparation method of Methylbenzoquate, is related to a kind of preparation method of broad-spectrum anticoccidial drug thing.This method in turn includes the following steps：Raw material is used as using the benzyloxy-aniline of 4 butyl 3, successively substitution reaction is carried out with the methoxy acrylic acid ethyl ester of 2 cyano group 3, ring closure reaction, last be hydrolyzed in acid condition are carried out again, and Methylbenzoquate is made with esterification, the present invention proposes a brand-new synthetic route, avoid using raw materials such as methoxy methylenes, each step reaction condition is gentle, technique is simple, and each step reaction is routine operation, effectively avoids the reaction condition of harshness.
Description
Technical field
The present invention relates to a kind of preparation method of coccidiostat, and in particular to a kind of method for preparing Methylbenzoquate.
Background technology
In the feeding process of Modern Animal Husbandry, livestock and poultry is highly susceptible to coccidium infection and receives invading for global-worm illness
Evil, the medicine of anticoccidial is of increased attention in recent years, and the veterinary drug of anticoccidial is also widely used in animal husbandry, and quinoline
Quinoline class anticoccidial drug is a kind of important veterinary drug bulk drug.Due to mainly there is quinoline ring in its molecular structure, therefore changing
Connect different substituents, so that it may different types of anticoccidial bulk drug can be formed.Wherein mainly there is fourth oxyquinoline (Byqyuni
Late fourths quinoline), second oxyquinoline (Decoquinate decoquinates, DECOX, deccox), Methylbenzoquate
Three kinds of (Methylbenzoquate Methylbenzoquates, Methylbenzoquate, Methylbenzoquate).Portioned product is real in such medicine
Show domestic, but most of medicine needs for import, and the drug effect of wherein Methylbenzoquate is optimal, and will not produce anti-medicine
Property.
On domestic market, Methylbenzoquate relies primarily on import, and due to price costly, occupation rate of market is not
Height, if production domesticization can be realized, effectively reduces use cost, will promote the development of such veterinary drug of China and animal husbandry.
The producer of such anticoccidial drug mass produced at present is mainly Lilly Co., Eli., Methylbenzoquate in the world
Main preparation methods be that condensing agent is used as by dimethyl methoxy methylene malonic acid, then under hot conditions (being more than 200 DEG C)
Cyclization is carried out, so that product (italian patent IT1320189 and world patent WO9911602) is obtained, due to methoxy methylene third
Acid dimethyl domestic supply amount is little, and price is costly, and has larger excitant, seriously limits this method
Scale of mass production.
After a large amount of pertinent literatures both at home and abroad and patent has been consulted, possess independent intellectual property right we have proposed one
Synthetic route synthesizes Methylbenzoquate, using domestic cheap and easily-available 2- cyano group -3- methoxy acrylic acid ethyl esters as condensing agent,
And improve the solvent of cyclization, although many one-step hydrolysis esterifications, but respectively step yield is higher, is routine operation,
There is preferable prospect of production.
The content of the invention
It is an object of the invention to provide a kind of equipment is simple, reaction condition avoids high temperature, be easy to operation and lossless environment
Coccidiostat Methylbenzoquate preparation method.
For up to above-mentioned purpose, We conducted a series of experiments, it is proposed that a brand-new synthetic route.
Realize that technical scheme is as follows：
A kind of preparation method of Methylbenzoquate, it is characterised in that：The Methylbenzoquate represented with formula (I) is according to following step
It is rapid to obtain：
A.3- the preparation of (3- benzyloxy -4- butyl benzenes amido) -2- cyanacrylates (III)
1 times of 4- butyl -3- benzyloxy-anilines, 2- cyano group -3- methoxy acrylic acid ethyl esters 0.60- are added in the reactor
0.73 times (weight ratio), is warming up to 30-35 DEG C of reaction after stirring, continue stirring reaction 4-8 hours, after completion of the reaction normal pressure
65 DEG C of methanol that reaction generation is distilled off are warming up to, residue is 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanoacrylates
Acetoacetic ester (III) crude product, can be directly used for next step reaction.
B.7- the preparation of benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II)
3- (3- benzyloxy -4- butyl benzenes amido) (III) 1 times of -2- cyanacrylates, phosphoric acid is added in the reactor
4-8 times of triethyl (weight ratio), after being stirred at room temperature uniformly, is warming up to 120 DEG C, continues stirring reaction 4-10 hours, reaction terminates
After be cooled to room temperature, first air-distillation removes the ethanol generated in ring closure reaction, then vacuum distillation removes solvent triethyl phosphate,
Obtained residue is 7- benzyloxies -6- butyl -4- cyano group -3- cyano quinolines (II) crude product, and 7- benzyls are obtained through ethyl alcohol recrystallization
Epoxide -6- butyl -4- cyano group -3- cyano quinolines (II) fine work.
C. the preparation of Methylbenzoquate (I)
(II) 1 times of 7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines, 5-10 times of methanol (weight are added in the reactor
Amount ratio) and weight fraction be 15% 5-10 times of hydrochloric acid (weight ratio), 45 DEG C are heated to after stirring, stirring reaction 3-5 is small
When, backflow is then warming up to again, continues stirring reaction 6-10 hours, most of solvent is distilled off in reaction after terminating, and filtering is received
Collect the solid separated out, be Methylbenzoquate (I) crude product, Methylbenzoquate (I) fine work is obtained after recrystallizing methanol.
Advantages of the present invention：
1. the present invention is used as condensing agent using 2- cyano group -3- methoxy acrylic acid ethyl esters, it is to avoid use expensive, thorn
Swash the big dimethyl methoxy methylene malonic acid of property, the product domestic market is in liberal supply and cheap, is conducive to the work of the technique
Industry is promoted.
2. each step reaction condition of the invention is gentle, technique is simple, each step reaction is routine operation, effectively avoids height
The reaction condition of temperature, improves production security.
Embodiment
Further illustrate how the present invention realizes below by specific embodiment：
Embodiment 1
A.3- the preparation of (3- benzyloxy -4- butyl benzenes amido) -2- cyanacrylates (III)
4- butyl -3- benzyloxy-anilines (255g, 1.0mol), 2- cyano group -3- methoxy acrylic acids are added in the reactor
Ethyl ester (186g, 1.2mol), is warming up to 30-35 DEG C of reaction after stirring, continue stirring reaction 8 hours, after completion of the reaction often
Pressure is warming up in 65 DEG C of methanol that reaction generation is distilled off, residue containing about 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanogen
Base ethyl acrylate (III) 337.2g, yield about 89.2% can be directly used for next step reaction.
B.7- the preparation of benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II)
In the reactor add 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanacrylates (III) (378g,
1.0mol), triethyl phosphate (3000g), after being stirred at room temperature uniformly, is warming up to 120 DEG C, continues stirring reaction 10 hours, reaction
Room temperature is cooled to after end, first air-distillation removes the ethanol generated in ring closure reaction, then vacuum distillation removes solvent tricresyl phosphate
Ethyl ester, obtained residue is 7- benzyloxies -6- butyl -4- cyano group -3- cyano quinolines (II) crude product, is obtained through ethyl alcohol recrystallization
7- benzyloxies -6- butyl -4- cyano group -3- cyano quinolines (II) fine work, is pale solid 296.7g, yield about 89.4%.
1H NMR (DMSO-d6,500MHz) δ：0.88-0.91 (3H, t), 1.32-1.59 (4H, m), 2.58-2.61 (2H,
T), 5.19 (1H, s), 7.44-7.53 (6H, m), 7.99 (1H, s), 9.21 (1H, s).FAB-MS(m/z)：:333(M+H).
C. the preparation of Methylbenzoquate (I)
7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II) (332g, 1.0mol), methanol are added in the reactor
(3300g) and weight fraction are 15% hydrochloric acid (3300g), are heated to 45 DEG C after stirring, stirring reaction 5 hours, then
Backflow is warming up to again, continues stirring reaction 10 hours, and most of solvent is distilled off after terminating in reaction, and consolidating for precipitation is collected by filtration
Body, is Methylbenzoquate (I) crude product, and Methylbenzoquate (I) fine work is obtained after recrystallizing methanol, is white or pale solid
312.5g, about 85.6%, M.P.287.3-288.1 DEG C of yield.
1H NMR (DMSO-d6,500MHz) δ：0.89-0.93 (3H, t), 1.33-1.61 (4H, m), 2.57-2.60 (2H,
T), 3.90 (3H, s), 5.17 (1H, s), 7.40-7.52 (6H, m), 8.14 (1H, s), 9.25 (1H, s).FAB-MS(m/z)：:
366(M+H)。
Embodiment 2
Other steps are same as Example 1, simply 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanoacrylates of step A
The preparation method of acetoacetic ester (III) is as follows：
4- butyl -3- benzyloxy-anilines (255g, 1.0mol), 2- cyano group -3- methoxy acrylic acids are added in the reactor
Ethyl ester (155g, 1.0mol), is warming up to 30-35 DEG C of reaction after stirring, continue stirring reaction 4 hours, after completion of the reaction often
Pressure is warming up in 65 DEG C of methanol that reaction generation is distilled off, residue containing about 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanogen
Base ethyl acrylate (III) 283.6g, yield about 75.0% can be directly used for next step reaction.
Embodiment 3
Other steps are same as Example 1, simply 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanoacrylates of step A
The preparation method of acetoacetic ester (III) is as follows：
4- butyl -3- benzyloxy-anilines (255g, 1.0mol), 2- cyano group -3- methoxy acrylic acids are added in the reactor
Ethyl ester (170.5g, 1.1mol), is warming up to 30-35 DEG C of reaction after stirring, continue stirring reaction 5 hours, after completion of the reaction
Normal pressure is warming up in 65 DEG C of methanol that reaction generation is distilled off, residue containing about 3- (3- benzyloxy -4- butyl benzenes amido) -2-
Cyanacrylate (III) 308.9g, yield about 81.7% can be directly used for next step reaction.
Embodiment 4
Other steps are same as Example 1, simply the 7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines of step B
(II) preparation method is as follows：
In the reactor add 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanacrylates (III) (378g,
1.0mol), triethyl phosphate (1550g), after being stirred at room temperature uniformly, is warming up to 120 DEG C, continues stirring reaction 4 hours, reaction knot
Room temperature is cooled to after beam, first air-distillation removes the ethanol generated in ring closure reaction, then vacuum distillation removes solvent tricresyl phosphate second
Ester, obtained residue is 7- benzyloxies -6- butyl -4- cyano group -3- cyano quinolines (II) crude product, and 7- is obtained through ethyl alcohol recrystallization
Benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II) fine work, is pale solid 230.8g, yield about 69.5%.
1H NMR (DMSO-d6,500MHz) δ：0.88-0.91 (3H, t), 1.32-1.59 (4H, m), 2.58-2.61 (2H,
T), 5.19 (1H, s), 7.44-7.53 (6H, m), 7.99 (1H, s), 9.21 (1H, s).FAB-MS(m/z)：:333(M+H).
Embodiment 5
Other steps are same as Example 1, simply the 7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines of step B
(II) preparation method is as follows：
In the reactor add 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanacrylates (III) (378g,
1.0mol), triethyl phosphate (2300g), after being stirred at room temperature uniformly, is warming up to 120 DEG C, continues stirring reaction 7 hours, reaction knot
Room temperature is cooled to after beam, first air-distillation removes the ethanol generated in ring closure reaction, then vacuum distillation removes solvent tricresyl phosphate second
Ester, obtained residue is 7- benzyloxies -6- butyl -4- cyano group -3- cyano quinolines (II) crude product, and 7- is obtained through ethyl alcohol recrystallization
Benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II) fine work, is pale solid 268.2g, yield about 80.8%.
1H NMR (DMSO-d6,500MHz) δ：0.88-0.91 (3H, t), 1.32-1.59 (4H, m), 2.58-2.61 (2H,
T), 5.19 (1H, s), 7.44-7.53 (6H, m), 7.99 (1H, s), 9.21 (1H, s).FAB-MS(m/z)：:333(M+H).
Embodiment 6
Other steps are same as Example 1, and simply the preparation method of the Methylbenzoquate (I) of step C is as follows：
7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II) (332g, 1.0mol), methanol are added in the reactor
(1700g) and weight fraction are 15% hydrochloric acid (1700g), are heated to 45 DEG C after stirring, stirring reaction 3 hours, then
Backflow is warming up to again, continues stirring reaction 6 hours, and most of solvent is distilled off after terminating in reaction, and consolidating for precipitation is collected by filtration
Body, is Methylbenzoquate (I) crude product, and Methylbenzoquate (I) fine work is obtained after recrystallizing methanol, is white or pale solid
243.6g, about 66.7%, M.P.287.3-288.1 DEG C of yield.
1H NMR (DMSO-d6,500MHz) δ：0.89-0.93 (3H, t), 1.33-1.61 (4H, m), 2.57-2.60 (2H,
T), 3.90 (3H, s), 5.17 (1H, s), 7.40-7.52 (6H, m), 8.14 (1H, s), 9.25 (1H, s).FAB-MS(m/z)：:
366(M+H)。
Embodiment 7
Other steps are same as Example 1, and simply the preparation method of the Methylbenzoquate (I) of step C is as follows：
7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II) (332g, 1.0mol), methanol are added in the reactor
(2500g) and weight fraction are 15% hydrochloric acid (2500g), are heated to 45 DEG C after stirring, stirring reaction 4 hours, then
Backflow is warming up to again, continues stirring reaction 8 hours, and most of solvent is distilled off after terminating in reaction, and consolidating for precipitation is collected by filtration
Body, is Methylbenzoquate (I) crude product, and Methylbenzoquate (I) fine work is obtained after recrystallizing methanol, is white or pale solid
276.3g, about 75.7%, M.P.287.3-288.1 DEG C of yield.
1H NMR (DMSO-d6,500MHz) δ：0.89-0.93 (3H, t), 1.33-1.61 (4H, m), 2.57-2.60 (2H,
T), 3.90 (3H, s), 5.17 (1H, s), 7.40-7.52 (6H, m), 8.14 (1H, s), 9.25 (1H, s).FAB-MS(m/z)：:
366(M+H)。
Embodiment 8
Other steps are same as Example 1, and simply the preparation method of the Methylbenzoquate (I) of step C is as follows：
7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II) (332g, 1.0mol), methanol are added in the reactor
(3000g) and weight fraction are 15% hydrochloric acid (3000g), are heated to 45 DEG C after stirring, stirring reaction 3 hours, then
Backflow is warming up to again, continues stirring reaction 9 hours, and most of solvent is distilled off after terminating in reaction, and consolidating for precipitation is collected by filtration
Body, is Methylbenzoquate (I) crude product, and Methylbenzoquate (I) fine work is obtained after recrystallizing methanol, is white or pale solid
256.8g, about 70.4%, M.P.287.3-288.1 DEG C of yield.
1H NMR (DMSO-d6,500MHz) δ：0.89-0.93 (3H, t), 1.33-1.61 (4H, m), 2.57-2.60 (2H,
T), 3.90 (3H, s), 5.17 (1H, s), 7.40-7.52 (6H, m), 8.14 (1H, s), 9.25 (1H, s).FAB-MS(m/z)：:
366(M+H)。
Embodiment 9
Other steps are same as Example 1, and simply the preparation method of the Methylbenzoquate (I) of step C is as follows：
7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II) (332g, 1.0mol), methanol are added in the reactor
(2800g) and weight fraction are 15% hydrochloric acid (2800g), are heated to 45 DEG C after stirring, stirring reaction 5 hours, then
Backflow is warming up to again, continues stirring reaction 8 hours, and most of solvent is distilled off after terminating in reaction, and consolidating for precipitation is collected by filtration
Body, is Methylbenzoquate (I) crude product, and Methylbenzoquate (I) fine work is obtained after recrystallizing methanol, is white or pale solid
289.5g, about 79.3%, M.P.287.3-288.1 DEG C of yield.
1H NMR (DMSO-d6,500MHz) δ：0.89-0.93 (3H, t), 1.33-1.61 (4H, m), 2.57-2.60 (2H,
T), 3.90 (3H, s), 5.17 (1H, s), 7.40-7.52 (6H, m), 8.14 (1H, s), 9.25 (1H, s).FAB-MS(m/z)：:
366(M+H)。
Described above, only presently preferred embodiments of the present invention is all according to institute of the present invention not for limiting the scope of the present invention
The equivalent changes and modifications done, are all that the scope of the claims of the present invention is covered.
Claims (1)
1. a kind of preparation method of Methylbenzoquate, it is characterised in that：The Methylbenzoquate represented with formula (I) is in accordance with the following steps
Obtain：
A.3- the preparation of (3- benzyloxy -4- butyl benzenes amido) -2- cyanacrylates (III)
1 times of 4- butyl -3- benzyloxy-anilines, 0.60-0.73 times of 2- cyano group -3- methoxy acrylic acids ethyl ester are added in the reactor
(weight ratio), is warming up to 30-35 DEG C of reaction after stirring, continue stirring reaction 4-8 hours, and normal pressure is warming up to after completion of the reaction
65 DEG C are distilled off the methanol that reaction is generated, and residue is 3- (3- benzyloxy -4- butyl benzenes amido) -2- cyanacrylates
(III) crude product, can be directly used for next step reaction.
B.7- the preparation of benzyloxy -6- butyl -4- cyano group -3- cyano quinolines (II)
3- (3- benzyloxy -4- butyl benzenes amido) (III) 1 times of -2- cyanacrylates, tricresyl phosphate second is added in the reactor
4-8 times of ester (weight ratio), after being stirred at room temperature uniformly, is warming up to 120 DEG C, continues stirring reaction 4-10 hours, and reaction terminates rear cold
But to room temperature, first air-distillation removes the ethanol generated in ring closure reaction, then vacuum distillation removes solvent triethyl phosphate, obtains
Residue be 7- benzyloxies -6- butyl -4- cyano group -3- cyano quinolines (II) crude product, through ethyl alcohol recrystallization obtain 7- benzyloxies -
6- butyl -4- cyano group -3- cyano quinolines (II) fine work.
C. the preparation of Methylbenzoquate (I)
(II) 1 times of 7- benzyloxy -6- butyl -4- cyano group -3- cyano quinolines, 5-10 times of methanol (weight ratio) are added in the reactor
5-10 times of hydrochloric acid (weight ratio) with weight fraction is 15%, is heated to 45 DEG C after stirring, stirring reaction 3-5 hours, so
It is warming up to backflow again afterwards, continues stirring reaction 6-10 hours, most of solvent is distilled off after terminating in reaction, and precipitation is collected by filtration
Solid, be Methylbenzoquate (I) crude product, Methylbenzoquate (I) fine work obtained after recrystallizing methanol.
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| CN101012224A (en) * | 2007-02-01 | 2007-08-08 | 中国药科大学 | Quinoline derivative, preparation method and medical use thereof |
| CN101223143A (en) * | 2005-05-18 | 2008-07-16 | 惠氏公司 | 3-cyanoquinoline inhibitors of TPL2 kinase and methods of making and using the same |
| WO2015188015A1 (en) * | 2014-06-04 | 2015-12-10 | Haro Pharmaceutical Inc. | 18-20 member bi-polycyclic compounds |
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| CN101223143A (en) * | 2005-05-18 | 2008-07-16 | 惠氏公司 | 3-cyanoquinoline inhibitors of TPL2 kinase and methods of making and using the same |
| CN101012224A (en) * | 2007-02-01 | 2007-08-08 | 中国药科大学 | Quinoline derivative, preparation method and medical use thereof |
| WO2015188015A1 (en) * | 2014-06-04 | 2015-12-10 | Haro Pharmaceutical Inc. | 18-20 member bi-polycyclic compounds |
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| Title |
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| 赵子艳: "萘喹酯合成工艺研究", 《中国优秀硕士学位论文全文数据库 工程科技Ⅰ辑》 * |
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