CN108658872B - Preparation method of avanafil intermediate - Google Patents
Preparation method of avanafil intermediate Download PDFInfo
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- CN108658872B CN108658872B CN201810414798.2A CN201810414798A CN108658872B CN 108658872 B CN108658872 B CN 108658872B CN 201810414798 A CN201810414798 A CN 201810414798A CN 108658872 B CN108658872 B CN 108658872B
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- ethoxycarbonyl
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- methoxybenzylamino
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- WEAJZXNPAWBCOA-INIZCTEOSA-N avanafil Chemical compound C1=C(Cl)C(OC)=CC=C1CNC1=NC(N2[C@@H](CCC2)CO)=NC=C1C(=O)NCC1=NC=CC=N1 WEAJZXNPAWBCOA-INIZCTEOSA-N 0.000 title claims abstract description 34
- 229960000307 avanafil Drugs 0.000 title claims abstract description 33
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 43
- 239000003054 catalyst Substances 0.000 claims abstract description 26
- HPWWGZRNBFATPZ-UHFFFAOYSA-N ethyl 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-methylsulfinylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(S(C)=O)N=C1NCC1=CC=C(OC)C(Cl)=C1 HPWWGZRNBFATPZ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 230000001590 oxidative effect Effects 0.000 claims abstract description 13
- 238000003756 stirring Methods 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
- WLOQDGSMJNYRRC-UHFFFAOYSA-N ethyl 4-[(3-chloro-4-methoxyphenyl)methylamino]-2-methylsulfanylpyrimidine-5-carboxylate Chemical compound CCOC(=O)C1=CN=C(SC)N=C1NCC1=CC=C(OC)C(Cl)=C1 WLOQDGSMJNYRRC-UHFFFAOYSA-N 0.000 claims abstract description 10
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000007810 chemical reaction solvent Substances 0.000 claims abstract description 7
- 239000007789 gas Substances 0.000 claims abstract description 7
- 239000001301 oxygen Substances 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 9
- 239000012295 chemical reaction liquid Substances 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 239000008213 purified water Substances 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- AMIMRNSIRUDHCM-UHFFFAOYSA-N Isopropylaldehyde Chemical compound CC(C)C=O AMIMRNSIRUDHCM-UHFFFAOYSA-N 0.000 claims description 8
- NBBJYMSMWIIQGU-UHFFFAOYSA-N Propionic aldehyde Chemical compound CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 230000003647 oxidation Effects 0.000 claims description 6
- 229960005070 ascorbic acid Drugs 0.000 claims description 5
- 235000010323 ascorbic acid Nutrition 0.000 claims description 5
- 239000011668 ascorbic acid Substances 0.000 claims description 5
- 230000003197 catalytic effect Effects 0.000 claims description 5
- 239000003638 chemical reducing agent Substances 0.000 claims description 5
- ZWYCMWUUWAFXIA-UHFFFAOYSA-N iron(2+);5,10,15,20-tetraphenylporphyrin-22,23-diide Chemical compound [Fe+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C2=CC=C([N-]2)C(C=2C=CC=CC=2)=C2C=CC3=N2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 ZWYCMWUUWAFXIA-UHFFFAOYSA-N 0.000 claims description 5
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 claims description 4
- IPFASKMZBDWRNG-UHFFFAOYSA-N manganese 5,10,15,20-tetraphenyl-21,23-dihydroporphyrin Chemical compound [Mn].c1cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1ccc(n1)c(-c1ccccc1)c1ccc([nH]1)c2-c1ccccc1 IPFASKMZBDWRNG-UHFFFAOYSA-N 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- CVKFXBUVLBFHGO-UHFFFAOYSA-N cobalt 5,10,15,20-tetraphenyl-21,23-dihydroporphyrin Chemical compound [Co].c1cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1ccc(n1)c(-c1ccccc1)c1ccc([nH]1)c2-c1ccccc1 CVKFXBUVLBFHGO-UHFFFAOYSA-N 0.000 claims description 3
- ZVWOIPVKXCLHLE-UHFFFAOYSA-N ruthenium 5,10,15,20-tetraphenyl-21,23-dihydroporphyrin Chemical compound [Ru].C1(=CC=CC=C1)C1=C2C=CC(C(=C3C=CC(=C(C=4C=CC(=C(C5=CC=C1N5)C5=CC=CC=C5)N4)C4=CC=CC=C4)N3)C3=CC=CC=C3)=N2 ZVWOIPVKXCLHLE-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- YNHJECZULSZAQK-UHFFFAOYSA-N tetraphenylporphyrin Chemical compound C1=CC(C(=C2C=CC(N2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3N2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 YNHJECZULSZAQK-UHFFFAOYSA-N 0.000 claims description 2
- 239000007800 oxidant agent Substances 0.000 abstract description 5
- 150000003462 sulfoxides Chemical class 0.000 abstract description 5
- 150000003568 thioethers Chemical class 0.000 abstract description 3
- 239000007858 starting material Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 26
- 239000007788 liquid Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000003570 air Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 239000000126 substance Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 230000006837 decompression Effects 0.000 description 4
- 238000006555 catalytic reaction Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 102000002004 Cytochrome P-450 Enzyme System Human genes 0.000 description 1
- 241001397104 Dima Species 0.000 description 1
- 208000010228 Erectile Dysfunction Diseases 0.000 description 1
- 101710198130 NADPH-cytochrome P450 reductase Proteins 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- HVVNJUAVDAZWCB-YFKPBYRVSA-N [(2s)-pyrrolidin-2-yl]methanol Chemical compound OC[C@@H]1CCCN1 HVVNJUAVDAZWCB-YFKPBYRVSA-N 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- -1 avanafil sulfoxide Chemical class 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 231100000024 genotoxic Toxicity 0.000 description 1
- 230000001738 genotoxic effect Effects 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- ODVRHJKVXOGKEJ-UHFFFAOYSA-N iron 5,10,15,20-tetraphenyl-21,23-dihydroporphyrin Chemical compound [Fe].c1cc2nc1c(-c1ccccc1)c1ccc([nH]1)c(-c1ccccc1)c1ccc(n1)c(-c1ccccc1)c1ccc([nH]1)c2-c1ccccc1 ODVRHJKVXOGKEJ-UHFFFAOYSA-N 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- RZNKMZKAXJTLQR-UHFFFAOYSA-N pyrimidin-2-ylmethanamine;hydrochloride Chemical compound Cl.NCC1=NC=CC=N1 RZNKMZKAXJTLQR-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229940046921 stendra Drugs 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/584—Recycling of catalysts
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention provides a preparation method of an avanafil intermediate, which comprises the following steps: dissolving a starting material 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine in a reaction solvent; adding metalloporphyrin as a catalyst, fully stirring to uniformly disperse, and transferring to a reaction kettle; introducing oxidizing gas at room temperature, and stirring for reaction to prepare 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine. The method takes substituted metalloporphyrin as a catalyst, takes air or oxygen as an oxidant, and catalytically oxidizes the thioether compound at normal temperature to prepare the sulfoxide intermediate of avanafil, and the target product and the catalyst are easy to separate after the reaction is finished.
Description
Technical Field
The invention relates to the technical field of pharmaceutical chemistry synthesis, in particular to a preparation method of an avanafil intermediate, and further relates to a preparation method of 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine.
Background
Avanafil CAS accession number: 330784-47-9, the structural formula of the compound is shown in figure 1. Is a drug developed by Vivus (Vivus) pharmaceutical company, granted by Mitsubishi pharmaceutical corporation, Ri Honda, for treating male erectile dysfunction. Was approved by the U.S. FDA for marketing in the united states at month 4 and 27 of 2012 under the trade name Stendra.
At present, the preparation route of the avanafil intermediate is shown in figure 2. The intermediate 1, 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulphinylpyrimidine plays an outstanding role in the avanafil synthesis process, and is prepared by oxidizing a methylthio group at the 2-position of a pyrimidine ring to a sulfoxide structure through an oxidation reaction of a starting material (4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine). The sulfoxide structure has strong leaving tendency, which is convenient for introducing L-prolinol through substitution reaction to obtain an intermediate 2. And then hydrolyzing an ethyl ester structure at the 5-position of the pyrimidine ring to free a carboxyl functional group, and performing amidation splicing with 2-aminomethyl pyrimidine hydrochloride to obtain the final product avanafil.
At present, m-chloroperoxybenzoic acid (m-CPBA) is mainly used as an oxidant in the preparation method of the avanafil intermediate 1, and most of domestic and foreign patents WO2015001567A1, EP1366760A1 and CN201310088950.X have reports on the aspect. The main disadvantages are:
(1) the reaction is difficult to control, and the methylthio is easy to be over-oxidized to obtain a sulfone structure;
(2) during the oxidation process, genotoxic nitrogen oxides are generated and remain in the bulk drugs, which is a serious challenge to the quality of the product;
(3) the purity of m-CPBA chemicals is generally not high, and the difficulty of post-treatment is increased by byproducts generated in the reaction process;
(4) as an oxidizing agent, m-CPBA reaction residues cause production danger if not disposed of in time, and therefore are not suitable for large-scale industrialization.
In view of the above, there is a need for an improvement of the preparation method of avanafil intermediate 1, i.e. 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine in the prior art, so as to solve the above problems.
Disclosure of Invention
The invention aims to disclose a preparation method of an avanafil intermediate 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulphinylpyrimidine, which is used for overcoming the defects that the reaction process is not easy to control in the prior art, and the difficulty in separating a target product from a catalyst is reduced, so that the recovery rate of the catalyst is improved, the preparation cost is reduced, and the content of various impurities in the target product is reduced.
In order to achieve the above object, the present invention provides a preparation method of avanafil intermediate 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine, comprising the following steps:
s1, dissolving a compound (I) 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine and a co-reducing agent in a reaction solvent, adding a metalloporphyrin catalyst, fully stirring and mixing, introducing an oxidizing gas under the normal temperature condition, reacting for 8-20 hours, and carrying out catalytic oxidation to obtain a compound (II), wherein the chemical reaction formula is shown as follows:
s2, after the reaction is completed, filtering to remove the metalloporphyrin catalyst in the reaction liquid, washing the reaction liquid by purified water, dehydrating and drying saturated NaCl, and concentrating under reduced pressure to obtain the 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine shown in the compound (II).
As a further improvement of the invention, the molar ratio of the compound (I) to the metalloporphyrin catalyst is 1: 0.001 to 0.01.
As a further development of the invention, the molar ratio of the compound (i) to the coreductant is 1: 1.0 to 5.0.
As a further improvement of the invention, the molar concentration of the compound (I) in the reaction solvent is 0.1-1.0 mol/L.
As a further improvement of the invention, the auxiliary reducing agent is one or a mixture of more than two of ascorbic acid, isobutyraldehyde and propionaldehyde in any proportion.
As a further improvement of the invention, the metalloporphyrin catalyst is one or a mixture of more than two of tetraphenylporphyrin iron, tetraphenylporphyrin manganese, tetraphenylporphyrin cobalt, tetraphenylporphyrin ruthenium and poly-tetraphenylporphyrin iron in any proportion.
As a further improvement of the invention, the reaction solvent is one or a mixture of more than two of ethyl acetate, tetrahydrofuran, dichloromethane, acetonitrile and toluene in any proportion.
As a further improvement of the present invention, the oxidizing gas is air or oxygen.
As a further improvement of the invention, the reaction pressure of the oxidizing gas is 1.0-5.0 atm.
Compared with the prior art, the invention has the beneficial effects that: the preparation method disclosed by the application is different from chemical oxidation, the reaction condition is mild, and the operation is relatively simple. The catalyst has small dosage, can be recycled, the oxidant is convenient and easy to obtain, the energy consumption in the whole catalysis process is low, and the catalyst has the characteristics of simplicity, greenness, environmental protection and the like, remarkably reduces the input cost of manpower, raw materials and the like, and is beneficial to large-scale industrial production.
Drawings
FIG. 1 is a chemical structural formula of avanafil;
FIG. 2 is a synthesis scheme for the synthesis of avanafil intermediates in the prior art;
FIG. 3 is a chemical structural formula of avanafil intermediate 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine, shown as compound (II);
FIG. 4 is a schematic diagram of the mechanism of preparing sulfoxide by oxidizing thioether under the catalysis of metalloporphyrin according to the present invention.
Detailed Description
The present invention is described in detail with reference to the embodiments shown in the drawings, but it should be understood that these embodiments are not intended to limit the present invention, and those skilled in the art should understand that functional, methodological, or structural equivalents or substitutions made by these embodiments are within the scope of the present invention.
Before describing in detail the various embodiments of the present application, the reaction mechanism of organic synthesis involved in the present invention is briefly described.
The application relates to a preparation process of an avanafil intermediate 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine, which relates to a catalytic oxidation reaction. The characteristics of the metalloporphyrin imitating cytochrome P-450 monooxygenase are utilized, and the metalloporphyrin is innovatively applied to the preparation of the avanafil sulfoxide intermediate, wherein the catalysis process is shown in figure 4.
Compared with the chemical oxidation method reported in the literature, the yield of the target product prepared by the metalloporphyrin catalytic oxidation is obviously higher, and the purity is relatively better.
The purity of the obtained avanafil intermediate shown in formula (II) is higher than 98 percent by HPLC detection.
Avanafil can be obtained by reacting this compound according to the method of WO2015001567a 1.
The detection conditions of HPLC are as follows: octadecylsilane chemically bonded silica gel as filler (Dima 99903: 250X 4.6mm, 5 μm for column chromatography); the detection wavelength is 240 nm; acetonitrile is taken as a mobile phase A, and 0.05mol/L sodium dihydrogen phosphate solution is taken as a mobile phase B; the flow rate is 1.0 ml/min; the column temperature was 30 ℃. Gradient elution was performed as follows:
| time (min) | Mobile phase A (%) |
| 0 | 38 |
| 10 | 38 |
| 17 | 75 |
| 40 | 75 |
| 45 | 38 |
| 55 | 38 |
Example 1:
4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol) and ascorbic acid (52.8g, 300mmol) were dissolved in 500mL of toluene, iron tetraphenylporphyrin (0.67g, 1mmol) was added thereto, and the mixture was sufficiently stirred to be uniformly dispersed, and then transferred to a pressure reactor. Introducing air at 25 deg.C, regulating reaction pressure to 1.0atm, and stirring for 8 hr. After the reaction is finished, the metalloporphyrin catalyst in the reaction liquid is removed by filtration, the organic phase is washed by purified water and saturated NaCl for 1 time in sequence, and white thick liquid is obtained by decompression and concentration, namely, the avanafil intermediate, namely 36.47g of 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine (the yield is 95.0 percent, the purity is 99.3 percent), and the avanafil intermediate is directly used for the next reaction.
IR(neat)cm-1:3350,1695,1590,1570,1500,1460,1440
MS(m/z):384(M+H)+
Example 2:
4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol) and isobutyraldehyde (7.2g, 100mmol) were dissolved in 1000mL of ethyl acetate, and manganese tetraphenylporphyrin (0.33g, 0.5mmol) was added thereto, and the mixture was sufficiently stirred to be uniformly dispersed, and then transferred to a pressure reactor. Introducing oxygen at 25 ℃, adjusting and controlling the reaction pressure at 5.0atm, and stirring for reaction for 16 h. After the reaction is finished, the metalloporphyrin catalyst in the reaction liquid is removed by filtration, the organic phase is washed by purified water and saturated NaCl for 1 time in sequence, and is decompressed and concentrated to obtain white thick liquid, namely, the avanafil intermediate, namely 35.05g of 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine (the yield is 91.3 percent, the purity is 98.0 percent), which is directly used for the next reaction.
Example 3:
4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol) and propionaldehyde (29.0g, 500mmol) were dissolved in 100mL of tetrahydrofuran, cobalt tetraphenylporphyrin (0.07g, 0.1mmol) was added thereto, and the mixture was sufficiently stirred to be uniformly dispersed, and then the mixture was transferred to a pressure reactor. Introducing air at 25 deg.C, regulating reaction pressure to 2.5atm, and stirring for 20 hr. After the reaction, the metalloporphyrin catalyst in the reaction solution was removed by filtration, and the reaction solution was concentrated to dryness under reduced pressure. Adding 500mL of ethyl acetate, fully stirring and dissolving, washing an organic phase for 1 time by using purified water and saturated NaCl in sequence, and concentrating under reduced pressure to obtain a white thick liquid, namely an avanafil intermediate, wherein 34.05g of 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine (the yield is 88.7%, the purity is 98.6%) is directly used for the next reaction.
Example 4:
4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol) and ascorbic acid (17.6g, 100mmol) were dissolved in 500mL of dichloromethane, and ruthenium tetraphenylporphyrin (0.7g, 1mmol) was added thereto and sufficiently stirred to disperse uniformly, followed by transferring to a pressure reactor. Introducing oxygen at 25 ℃, adjusting and controlling the reaction pressure to be 1.0atm, and stirring and reacting for 8 hours. After the reaction is finished, the metalloporphyrin catalyst in the reaction liquid is removed by filtration, the organic phase is washed by purified water and saturated NaCl for 1 time in sequence, and a white thick liquid is obtained by decompression and concentration, namely an avanafil intermediate, namely 36.16g of 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine (the yield is 94.2%, the purity is 99.1%), and the avanafil intermediate is directly used for the next reaction.
Example 5:
4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol) and isobutyraldehyde (36.1g, 500mmol) were dissolved in 100mL of acetonitrile, and iron tetraphenylporphyrin (0.34g, 0.5mmol of active unit equivalent iron tetraphenylporphyrin) was added thereto, and the mixture was sufficiently stirred to be uniformly dispersed, and then transferred to a pressure reactor. Introducing air at 25 ℃, adjusting and controlling the reaction pressure at 5.0atm, and stirring for reacting for 16 h. After the reaction, the metalloporphyrin catalyst in the reaction solution was removed by filtration, and the reaction solution was concentrated to dryness under reduced pressure. Adding 500mL of ethyl acetate, fully stirring and dissolving, washing an organic phase for 1 time by using purified water and saturated NaCl in sequence, and concentrating under reduced pressure to obtain a white thick liquid, namely an avanafil intermediate, wherein 35.89g (the yield is 93.5 percent, the purity is 98.2 percent) of 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine is directly used for the next reaction.
Example 6:
4- (3-chloro-4-methoxylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol) and propionaldehyde (17.42g, 300mmol) were dissolved in 1000mL of toluene, iron tetraphenylporphyrin (0.07g, 0.1mmol) was added thereto, and the mixture was sufficiently stirred to be uniformly dispersed, and then transferred to a pressure reactor. Introducing oxygen at 25 ℃, adjusting and controlling the reaction pressure to be 2.5atm, and stirring and reacting for 20 hours. After the reaction is finished, the metalloporphyrin catalyst in the reaction liquid is removed by filtration, the organic phase is washed by purified water and saturated NaCl for 1 time in sequence, and white thick liquid is obtained by decompression and concentration, namely, the avanafil intermediate, namely 34.39g of 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine (the yield is 89.6 percent, the purity is 98.4 percent), and the avanafil intermediate is directly used for the next reaction.
Example 7:
4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol), ascorbic acid (52.8g, 300mmol) and 500mL of ethyl acetate were dissolved, manganese tetraphenylporphyrin (0.67g, 1mmol) was added thereto, and the mixture was sufficiently stirred to be uniformly dispersed, and then transferred to a pressure reactor. Introducing air at 25 deg.C, regulating reaction pressure to 1.0atm, and stirring for 8 hr. After the reaction is finished, the metalloporphyrin catalyst in the reaction liquid is removed by filtration, the organic phase is washed by purified water and saturated NaCl for 1 time in sequence, and a white thick liquid is obtained by decompression and concentration, namely, an avanafil intermediate, namely 35.35g of 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine (the yield is 92.1 percent, the purity is 99.2 percent), and the avanafil intermediate is directly used for the next reaction.
In the application, a metalloporphyrin catalyst is used as a catalyst, air or oxygen is used as an oxidant, and a thioether compound is catalytically oxidized at normal temperature to prepare a sulfoxide intermediate of avanafil. After the reaction is finished, the target product and the catalyst are easy to separate, the difficulty of separation and purification of the later-stage product is greatly reduced, the recovered catalyst can be recycled, and the preparation cost can be obviously reduced. The route of the invention has good catalytic selectivity, simple reaction operation and low energy consumption. The whole process is simple, green and environment-friendly, and has good industrialization prospect.
The above-listed detailed description is only a specific description of a possible embodiment of the present invention, and they are not intended to limit the scope of the present invention, and equivalent embodiments or modifications made without departing from the technical spirit of the present invention should be included in the scope of the present invention.
It will be evident to those skilled in the art that the invention is not limited to the details of the foregoing illustrative embodiments, and that the present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Any reference sign in a claim should not be construed as limiting the claim concerned.
Furthermore, it should be understood that although the present description refers to embodiments, not every embodiment may contain only a single embodiment, and such description is for clarity only, and those skilled in the art should integrate the description, and the embodiments may be combined as appropriate to form other embodiments understood by those skilled in the art.
Claims (7)
1. A preparation method of an avanafil intermediate 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine is characterized by comprising the following steps:
s1, dissolving a compound (I) 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine and a co-reducing agent in a reaction solvent, adding a metalloporphyrin catalyst, fully stirring and mixing, introducing an oxidizing gas under the normal temperature condition, reacting for 8-20 hours, and carrying out catalytic oxidation to obtain a compound (II), wherein the chemical reaction formula is shown as follows:
s2, after the reaction is completed, filtering to remove the metalloporphyrin catalyst in the reaction liquid, washing the reaction liquid by purified water, dehydrating and drying saturated NaCl, and concentrating under reduced pressure to obtain 4- (3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine shown in a compound (II);
wherein: the auxiliary reducing agent is one or a mixture of more than two of ascorbic acid, isobutyraldehyde and propionaldehyde in any proportion, and the metalloporphyrin catalyst is one or a mixture of more than two of iron tetraphenylporphyrin, manganese tetraphenylporphyrin, cobalt tetraphenylporphyrin, ruthenium tetraphenylporphyrin and iron poly-tetraphenylporphyrin in any proportion.
2. The process according to claim 1, wherein the molar ratio of compound (i) to metalloporphyrin catalyst is 1: 0.001 to 0.01.
3. The process according to claim 1, wherein the molar ratio of compound (i) to co-reducing agent is 1: 1.0 to 5.0.
4. The process according to claim 1, wherein the molar concentration of the compound (I) in the reaction solvent is 0.1 to 1.0 mol/L.
5. The preparation method according to claim 1, wherein the reaction solvent is one or a mixture of two or more of ethyl acetate, tetrahydrofuran, dichloromethane, acetonitrile and toluene in any proportion.
6. The production method according to claim 1, wherein the oxidizing gas is air or oxygen.
7. The method according to claim 1, wherein the reaction pressure at which the oxidizing gas is introduced is 1.0 to 5.0 atm.
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