CN109761778A - A kind of method of synthesizing optical active alpha-hydroxypropanamide derivative - Google Patents
A kind of method of synthesizing optical active alpha-hydroxypropanamide derivative Download PDFInfo
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- CN109761778A CN109761778A CN201811502645.XA CN201811502645A CN109761778A CN 109761778 A CN109761778 A CN 109761778A CN 201811502645 A CN201811502645 A CN 201811502645A CN 109761778 A CN109761778 A CN 109761778A
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- Prior art keywords
- methyl
- hydroxy
- bromo
- cyano
- propionamide
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- 238000000034 method Methods 0.000 title claims abstract description 20
- SXQFCVDSOLSHOQ-UHFFFAOYSA-N lactamide Chemical class CC(O)C(N)=O SXQFCVDSOLSHOQ-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 230000003287 optical effect Effects 0.000 title claims abstract description 18
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 16
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims abstract description 17
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 229940080818 propionamide Drugs 0.000 claims abstract description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- HBJAYXGUOOININ-UHFFFAOYSA-N 3-bromo-2-hydroxy-2-methylpropanoic acid Chemical compound BrCC(O)(C)C(O)=O HBJAYXGUOOININ-UHFFFAOYSA-N 0.000 claims abstract description 14
- ZFNYKZIQYSIJMK-UHFFFAOYSA-N C(#N)C1=CC=CC=C1.[O] Chemical compound C(#N)C1=CC=CC=C1.[O] ZFNYKZIQYSIJMK-UHFFFAOYSA-N 0.000 claims abstract description 11
- ADVGKWPZRIDURE-UHFFFAOYSA-N 2'-Hydroxyacetanilide Chemical compound CC(=O)NC1=CC=CC=C1O ADVGKWPZRIDURE-UHFFFAOYSA-N 0.000 claims abstract description 6
- CVNOWLNNPYYEOH-UHFFFAOYSA-N 4-cyanophenol Chemical compound OC1=CC=C(C#N)C=C1 CVNOWLNNPYYEOH-UHFFFAOYSA-N 0.000 claims abstract description 6
- VHRYZQNGTZXDNX-UHFFFAOYSA-N methacryloyl chloride Chemical compound CC(=C)C(Cl)=O VHRYZQNGTZXDNX-UHFFFAOYSA-N 0.000 claims abstract description 6
- UTKUVRNVYFTEHF-UHFFFAOYSA-N 4-nitro-3-(trifluoromethyl)aniline Chemical compound NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 UTKUVRNVYFTEHF-UHFFFAOYSA-N 0.000 claims abstract description 5
- 238000005893 bromination reaction Methods 0.000 claims abstract description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims abstract 5
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 230000015572 biosynthetic process Effects 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- -1 2- methylacryloyl Chemical group 0.000 claims description 15
- 229950002366 nafoxidine Drugs 0.000 claims description 15
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 5
- VJGNLOIQCWLBJR-UHFFFAOYSA-M benzyl(tributyl)azanium;chloride Chemical group [Cl-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 VJGNLOIQCWLBJR-UHFFFAOYSA-M 0.000 claims description 5
- 230000000694 effects Effects 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-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
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 claims description 2
- 150000001408 amides Chemical class 0.000 claims description 2
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims 9
- 239000003153 chemical reaction reagent Substances 0.000 claims 8
- 238000005660 chlorination reaction Methods 0.000 claims 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims 3
- 239000003513 alkali Substances 0.000 claims 3
- 239000003444 phase transfer catalyst Substances 0.000 claims 3
- 239000003495 polar organic solvent Substances 0.000 claims 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims 2
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 claims 2
- PAMIQIKDUOTOBW-UHFFFAOYSA-N N-methylcyclohexylamine Natural products CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 claims 2
- 238000005815 base catalysis Methods 0.000 claims 2
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 claims 2
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 claims 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims 1
- AUBSNUSTVUZGCC-UHFFFAOYSA-N [NH4+].[Br-].C(C)[PH3+].[Br-] Chemical compound [NH4+].[Br-].C(C)[PH3+].[Br-] AUBSNUSTVUZGCC-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 239000000908 ammonium hydroxide Substances 0.000 claims 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 1
- UDYGXWPMSJPFDG-UHFFFAOYSA-M benzyl(tributyl)azanium;bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CC1=CC=CC=C1 UDYGXWPMSJPFDG-UHFFFAOYSA-M 0.000 claims 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims 1
- 229910052794 bromium Inorganic materials 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- 239000012046 mixed solvent Substances 0.000 claims 1
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 claims 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 abstract description 2
- VIUDTWATMPPKEL-UHFFFAOYSA-N 3-(trifluoromethyl)aniline Chemical compound NC1=CC=CC(C(F)(F)F)=C1 VIUDTWATMPPKEL-UHFFFAOYSA-N 0.000 abstract 1
- 230000010933 acylation Effects 0.000 abstract 1
- 238000005917 acylation reaction Methods 0.000 abstract 1
- 238000005915 ammonolysis reaction Methods 0.000 abstract 1
- 230000031709 bromination Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
- 239000000243 solution Substances 0.000 description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 239000007787 solid Substances 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000012043 crude product Substances 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- 229910052757 nitrogen Inorganic materials 0.000 description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- JNGVJMBLXIUVRD-SFHVURJKSA-N (2s)-3-(4-cyanophenoxy)-n-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide Chemical compound C([C@@](O)(C)C(=O)NC=1C=C(C(C#N)=CC=1)C(F)(F)F)OC1=CC=C(C#N)C=C1 JNGVJMBLXIUVRD-SFHVURJKSA-N 0.000 description 6
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 229950001115 enobosarm Drugs 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YVXVTLGIDOACBJ-SFHVURJKSA-N (2S)-3-(4-acetamidophenoxy)-2-hydroxy-2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]propanamide Chemical compound C1=CC(NC(=O)C)=CC=C1OC[C@](C)(O)C(=O)NC1=CC=C([N+]([O-])=O)C(C(F)(F)F)=C1 YVXVTLGIDOACBJ-SFHVURJKSA-N 0.000 description 3
- LCPVQAHEFVXVKT-UHFFFAOYSA-N 2-(2,4-difluorophenoxy)pyridin-3-amine Chemical compound NC1=CC=CN=C1OC1=CC=C(F)C=C1F LCPVQAHEFVXVKT-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- CHQMHPLRPQMAMX-UHFFFAOYSA-L sodium persulfate Substances [Na+].[Na+].[O-]S(=O)(=O)OOS([O-])(=O)=O CHQMHPLRPQMAMX-UHFFFAOYSA-L 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- YHWMFDLNZGIJSD-UHFFFAOYSA-N 2h-1,4-oxazine Chemical class C1OC=CN=C1 YHWMFDLNZGIJSD-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 102000001307 androgen receptors Human genes 0.000 description 2
- 108010080146 androgen receptors Proteins 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 201000000585 muscular atrophy Diseases 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000012827 research and development Methods 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 206010003694 Atrophy Diseases 0.000 description 1
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
- 125000005997 bromomethyl group Chemical group 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 208000000649 small cell carcinoma Diseases 0.000 description 1
- 230000003637 steroidlike Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a kind of methods of synthesizing optical active alpha-hydroxypropanamide derivative, belong to organic synthesis field.By using proline as chiral auxiliary; nucleophilic substitution occurs through acylation, bromination, de- chiral auxiliary and 4- cyano -3- 5-trifluoromethylaniline with methacrylic chloride, obtains the bromo- 2- hydroxy-2-methyl-N- of 3- [(4- cyano -3- trifluoromethyl) phenyl] propionamide.Nucleophilic substitution occurs with 4-hydroxybenzonitrile again, optically active compound 3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide is made.Ammonolysis occurs using the bromo- 2- hydroxy-2-methyl propionic acid of optically active 3- and 4- nitro-3-trifluoromethylaniline, nucleophilic substitution occurs with to acetaminophenol, optically active compound 3- (4- acetoxyl group phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide is made.The present invention is a kind of to efficiently synthesize optical activity alpha-hydroxypropanamide derivative method.
Description
Technical field
The present invention relates to a kind of methods of synthesizing optical active alpha-hydroxypropanamide derivative, belong to organic synthesis field.
Background technique
(2S) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
(Enobosarm, S-V) is a kind of selective non-steroidal androgen receptor regulator by the research and development of GTx company, the U.S., is used for
The diseases such as muscular atrophy and osteoporosis are treated, are currently carried out for amyotrophic clinical examination caused by kinds cancer
It tests.In completed 8 I phases and II clinical trial phase the results show that Enobosarm can be obviously improved the thin body of cancer patient
Weight and muscle strength and function.In the amyotrophic III phase clinic examination for the treatment of Patients with Non-small-cell Lung that in July, 2011 starts
Test, investigated Enobosarm whether be able to ascend patient body function and maintenance or increase Lean mass, data is
In arrangement, if Enobosarm can reach expected test objective, it will become first and be used to prevent and treat muscle loss
Or the drug of atrophy.
(2S) -3- (4- acetylamino phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionyl
Amine (Andarine, S- VII) is equally a kind of selective androgen receptor regulator by the research and development of GTx company, the U.S., is used for
Treat the diseases such as muscular atrophy, osteoporosis and benign prostatauxe.The structure of Andarine and Enobosarm extremely phase
Seemingly, to its synthetic method research can thus class formation new drug exploitation provide technical support.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative,
The present invention is that operation is easy and efficient for one kind, the Lactoyl amine derivative synthetic method of high quality.
The technical solution used in the present invention is: a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative:
By nucleophilic substitution occurring with methacrylic chloride, obtains 1- (2- methyl 1. using proline as chiral auxiliary
Acryloyl group) nafoxidine -2- carboxylic acid；2. 1- (2- methylacryloyl) nafoxidine -2- carboxylic acid and N- bromo succinyl are sub-
Bromination reaction occurs for amine (NBS), obtains bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-Isosorbide-5-Nitrae-diketone；3. passing through
Hydrobromic acid hydrolysis, sloughs chiral auxiliary, obtains the bromo- 2- hydroxy-2-methyl propionic acid of optically active 3-.
Optically active bromo- 2- hydroxy-2-methyl propionic acid of 3- and thionyl chloride effect generate acyl chlorides, then with 4- cyano-
Nucleophilic substitution occurs for 3- 5-trifluoromethylaniline, obtains the bromo- 2- hydroxy-2-methyl-N- of 3- [(4- cyano -3- trifluoromethyl) benzene
Base] propionamide；The bromo- 2- hydroxy-2-methyl-N- of 3- [(4- cyano -3- trifluoromethyl) phenyl] propionamide under potassium carbonate catalysis
Nucleophilic substitution occurs with 4-hydroxybenzonitrile, optically active compound 3- (4- cyano-benzene oxygen)-N- [4- cyano -3- is made
Trifluoromethyl] -2- hydroxy-2-methyl propionamide.
Optically active bromo- 2- hydroxy-2-methyl propionic acid of 3- and thionyl chloride effect generate acyl chlorides, then with 4- nitro-
Nucleophilic substitution occurs for 3- 5-trifluoromethylaniline, obtains the bromo- 2- hydroxy-2-methyl-N- of 3- [(4- nitro -3- trifluoromethyl) benzene
Base] propionamide；The bromo- 2- hydroxy-2-methyl-N- of 3- [(4- nitro -3- trifluoromethyl) benzene under the catalysis of benzyl tributyl ammonium chloride
Base] propionamide with to acetaminophenol occur nucleophilic substitution, be made optically active compound 3- (4- acetyloxy phenyl oxygen
Base)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide.The present invention is that one kind efficiently synthesizes optics work
The method of property Lactoyl amine derivative.Synthetic route is as follows:
(2S) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
The synthesis of (Enobosarm, S-V)
(2R) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
(R-V) synthesis
(2S) -3- (4- acetylamino phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionyl
The synthesis of amine (Andarine, S- VII)
(2R) -3- (4- acetylamino phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionyl
The synthesis of amine (R- VII)
Specific embodiment
Embodiment
The synthesis of (2R) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid (R- I)
D-PROLINE (20.80g, 180.8mmol) is dissolved in 2mol/L sodium hydroxide solution (90mL), acetone is added
(90mL), ice bath are cooled to 5~10 DEG C, under stirring, and methacrylic chloride (28.20g, 271.1mmol) and tetrahydrofuran is added dropwise
The mixed solution of (30mL), while pH11~12 of 2mol/L sodium hydroxide solution (113mL) control reaction solution are added dropwise.It drips
Finish, 3h is stirred at room temperature.Remove organic solvent under reduced pressure, Liquid Residue is adjusted to pH 5 with 6mol/L sulfuric acid solution, is extracted with ethyl acetate.
Liquid Residue continues to be acidified to pH 2 with 6mol/L sulfuric acid solution, is extracted with ethyl acetate (40mL × 5), merges organic layer, with nothing
Aqueous sodium persulfate dries, filters, and is concentrated under reduced pressure, obtains I 27.74g of white solid R-, yield 83.8%, mp.102~103 DEG C.(3R,
The synthesis of 8R)-bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [1,4] oxazines -1,4- diketone (II a)
Compound R-I (27.70g, 151.2mmol) is dissolved in N, in N- methylacetamide (120mL).Nitrogen protection condition
Under, the mixing that N- bromo-succinimide (NBS) (53.82g, 302.4mmol) and N, N- methylacetamide (200mL) is added dropwise is molten
Liquid.It is added dropwise, 5h is stirred at room temperature, reaction solution is poured into distilled water (600mL), solid is precipitated, and stirs 0.5h, filters, obtains
II a 24.16g of white solid, yield 60.9%, mp.151~153 DEG C are obtained with re-crystallizing in ethyl acetate to crude product.
(R)-(+) synthesis of the bromo- 2- hydroxy-2-methyl propionic acid (R- III) of -3-
Compound ii a (21.00g, 80.1mmol) is dissolved in 24% hydrobromic acid solution (168mL), reflux is warming up to, is protected
Temperature reaction 5h.End of reaction is cooled to room temperature, and is added distilled water (210mL), (40mL × 3) are extracted with ethyl acetate, are associated with
Machine layer extracts (40mL × 3) with saturated sodium bicarbonate solution, and combining water layer is acidified to pH 2 with concentrated hydrochloric acid, is extracted with ethyl acetate
It takes (30mL × 4), merges organic layer, anhydrous sodium sulfate dries, filters, and evaporating solvent under reduced pressure obtains crude product, is tied again with toluene
Crystalline substance filters, dry, obtains III 13.41g of white, needle-shaped crystals R-, yield 91.3%, mp.107~109 DEG C.
(R)-(-) the bromo- 2- hydroxy-2-methyl-N- of -3- [(4- cyano -3- trifluoromethyl) phenyl] propionamide (R- IV)
Synthesis
By compound R-III (6.00g, 32.9mmol), 4- cyano -3- 5-trifluoromethylaniline (6.79g, 36.5mmol) and
N, N- methylacetamide (42mL) are added in reaction flask, and ice bath is cooled to -15 DEG C, be added dropwise thionyl chloride (4.60g,
39.0mmol), -10 DEG C~-15 DEG C of reaction temperature are controlled.It is added dropwise, after insulated and stirred 0.5h, rises to 40 DEG C of reaction 3h.It will
Reaction solution is poured slowly into cold saturated sodium bicarbonate solution (120mL), is extracted with ethyl acetate (30mL × 3), is merged organic
Phase, saturated sodium chloride solution washing, filters, evaporating solvent under reduced pressure obtains crude product, with the mixing of petroleum ether and methyl tertiary butyl ether(MTBE)
Solution recrystallization, decolorizing with activated carbon obtain IV 9.30g of white solid R-, yield 80.4%, mp.133~135 DEG C.
(2S) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
(S-V) synthesis
Compound R-IV (30.0g, 85mmol) and 4-hydroxybenzonitrile (12.2g, 102mmol) are dissolved in isopropanol
In (300mL), it is added Anhydrous potassium carbonate (35.4g, 256mmol), under the conditions of nitrogen protection, back flow reaction 0.5h.Evaporated under reduced pressure
Solvent, residue are dissolved in distilled water (300mL), are extracted with ethyl acetate (150mL × 2), merge organic phase, with 10% hydrogen-oxygen
Change sodium solution washing (100mL × 3), washed (200mL) with saturated sodium chloride solution, anhydrous sodium sulfate is dry, filters, filtrate rotation
It is dry, crude product is obtained, with re crystallization from toluene, active carbon decoloring obtains white solid S-V25.1g, yield 75.5%, mp.90~91 DEG C.
The synthesis of (2S) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid (S- I)
L-PROLINE (10.40g, 90.4mmol) is dissolved in 2mol/L sodium hydroxide solution (45mL), acetone is added
(45mL), ice bath is cooling, stirring.At 5~10 DEG C, methacrylic chloride (14.10g, 135.5mmol) and tetrahydrofuran is added dropwise
The mixed solution of (15mL), while 2mol/L sodium hydroxide solution (59mL) control reaction solution pH11~12 are added dropwise.It is added dropwise,
3h is stirred at room temperature, removes organic solvent under reduced pressure, Liquid Residue is acidified to pH 5 with 6mol/L sulfuric acid solution, is extracted with ethyl acetate.
Liquid Residue continues to be acidified to pH 2 with 6mol/L sulfuric acid solution, is extracted with ethyl acetate (20mL × 5), merges organic layer, with nothing
Aqueous sodium persulfate dries, filters, and is concentrated to dryness, and obtains I 13.18g of white solid S-, yield 79.6%, mp.101~103 DEG C.
The synthesis of (3S, 8S)-bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [1,4] oxazines -1,4- diketone (II b)
Compound S- I (13.00g, 71.0mmol) is dissolved in n,N-dimethylacetamide (56mL).Nitrogen protection condition
Under, the mixed solution of NBS (25.26g, 141.9mmol) and n,N-dimethylacetamide (95mL) is added dropwise.It is added dropwise, room temperature
5h is stirred, reaction solution is poured into distilled water (300mL), solid is precipitated, and stirs 0.5h, filters, obtains crude product, use ethyl acetate
Recrystallization, obtains II b 9.93g of white solid, yield 53.4%, mp.155~156 DEG C.
(S)-(+) synthesis of the bromo- 2- hydroxy-2-methyl propionic acid (S- III) of -3-
Compound ii b (9.90g, 37.8mmol) is dissolved in 24% hydrobromic acid solution (80mL), reflux is warming up to, is kept the temperature
React 5h.End of reaction is cooled to room temperature, and is added distilled water (100mL), is extracted with ethyl acetate (25mL × 3), is merged organic
Layer.Organic layer extracts (25mL × 3) with saturated sodium bicarbonate solution, combining water layer.Water layer enriching hydrochloric acid is acidified to pH 2, uses second
Acetoacetic ester extracts (20mL × 4), merges organic layer, adds anhydrous sodium sulfate dry, filters, filtrate is spin-dried for, obtains crude product, use toluene
Recrystallization, it is dry, obtain III 6.12g of white, needle-shaped crystals S-, yield 88.5%, mp.108~109 DEG C.
(S)-(-) the bromo- 2- hydroxy-2-methyl-N- of -3- [(4- cyano -3- trifluoromethyl) phenyl] propionamide (S- IV)
Synthesis
By compound S- III (30.0g, 164mmol), 4- cyano -3- 5-trifluoromethylaniline (33.9g, 182mmol) and N,
N- methylacetamide (210mL) is added in reaction flask, and ice bath is cooled to -15 DEG C, is added dropwise thionyl chloride (23.0g, 195mmol),
Reaction temperature is controlled at -10 DEG C~-15 DEG C.It finishes, insulated and stirred 0.5h, rises to 40 DEG C of reaction 2h.Reaction solution is poured slowly into
It in cold saturated sodium bicarbonate solution (60mL), is extracted with ethyl acetate (200mL × 3), merges organic phase, saturated sodium-chloride is molten
Liquid washing, anhydrous sodium sulfate are dried, filtered, are concentrated to dryness, and crude product are obtained, with the mixing of petroleum ether and methyl tertiary butyl ether(MTBE)
Solution recrystallization, decolorizing with activated carbon obtain IV 42.3g of white solid S-, yield 73.1%, mp.106~108 DEG C.
(2R) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
(R-V) synthesis
Compound S- IV (30.0g, 85mmol) and 4-hydroxybenzonitrile (12.2g, 102mmol) are dissolved in isopropanol
In (300mL), it is added Anhydrous potassium carbonate (35.4g, 256mmol), under the conditions of nitrogen protection, back flow reaction 0.5h.Evaporated under reduced pressure
Solvent, residue are dissolved in distilled water (300mL), are extracted with ethyl acetate (150mL × 2), merge organic phase, with 10% hydrogen-oxygen
Change sodium solution washing (100mL × 3), wash (200mL) with saturated sodium chloride solution, anhydrous sodium sulfate dries, filters, and depressurizes dense
It is reduced to dry, obtains crude product, with re crystallization from toluene, active carbon decoloring obtains white solid R-V23.2g, yield 69.7%, mp.91~92
℃。
(R)-(-) the bromo- 2- hydroxy-2-methyl-N- of -3- [(4- nitro -3- trifluoromethyl) phenyl] propionamide (R- VI)
Synthesis
By compound R-III (30.0g, 164mmol), 4- nitro-3-trifluoromethylaniline (26.0g, 126mmol) and N,
N- methylacetamide (200mL) is added in reaction flask, and ice bath is cooled to -15 DEG C, is added dropwise thionyl chloride (22.3g, 189mmol),
Temperature is controlled at -10 DEG C~-15 DEG C.It finishes, insulated and stirred 0.5h, rises to 40 DEG C of reaction 8h.Reaction solution is poured slowly into cold
It in saturated sodium bicarbonate solution (600mL), is extracted with ethyl acetate (150mL × 3), merges organic phase, saturated sodium chloride solution
Washing, anhydrous sodium sulfate are dried, filtered, are concentrated to dryness, be purified by silica gel column chromatography, and obtain VI 34.8g of yellow solid R-, are received
Rate 57.2%, mp.98~99 DEG C.
2.3.2 (2S) -3- (4- acetylamino phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxyl -2- first
The synthesis of base propionamide (S- VII)
Isopropanol is dissolved in by compound R-VI (20.0g, 54mmol) and to acetaminophenol (12.2g, 81mmol)
In (300mL), Anhydrous potassium carbonate (14.9g, 108mmol) and 10% benzyl tributyl ammonium chloride (2.0g), nitrogen protection is added
Under the conditions of, back flow reaction 4h.Evaporated under reduced pressure solvent, residue are dissolved in distilled water (200mL), and (100mL is extracted with ethyl acetate
× 2), merge organic phase, (1,0mL × 3) are washed with 10% sodium hydroxide solution, with anhydrous saturated sodium chloride solution (150mL)
Washing, anhydrous sodium sulfate are dried, filtered, are concentrated to dryness, and obtain crude product, and with re crystallization from toluene, it is solid to obtain yellow for active carbon decoloring
VII 18.5g of body S-, yield 77.8%, mp.70~72 DEG C.
(S)-(-) the bromo- 2- hydroxy-2-methyl-N- of -3- [(4- nitro -3- trifluoromethyl) phenyl] propionamide (S- VI)
Synthesis
By compound S- III (30.0g, 164mmol), 4- nitro-3-trifluoromethylaniline (26.0g, 126mmol) and N,
N- methylacetamide (200mL) is added in reaction flask, and ice bath is cooled to -15 DEG C, is added dropwise thionyl chloride (22.3g, 189mmol),
Temperature is controlled at -10 DEG C~-15 DEG C.It finishes, insulated and stirred 0.5h, rises to 40 DEG C of reaction 8h.Reaction solution is poured slowly into cold
It in saturated sodium bicarbonate solution (600mL), is extracted with ethyl acetate (150mL × 3), merges organic phase, saturated sodium chloride solution
Washing, anhydrous sodium sulfate dry, filter, and evaporating solvent under reduced pressure is purified by silica gel column chromatography, and obtain VI 34.6g of yellow solid S-, receive
Rate 56.9%, mp.100~102 DEG C.
(2R) -3- (4- acetylamino phenoxy group)-N- [(4- nitro -3- trifluoromethyl) phenyl] -2- hydroxy-2-methyl third
The synthesis of amide (R- VII)
Isopropanol is dissolved in by compound S- VI (10.0g, 27mmol) and to acetaminophenol (6.1g, 41mmol)
In (150mL), Anhydrous potassium carbonate (7.4g, 54mmol) and 10% benzyl tributyl ammonium chloride (1.0g), nitrogen protection item is added
Under part, back flow reaction 4h.Evaporated under reduced pressure solvent, residue are dissolved in distilled water (150mL), be extracted with ethyl acetate (100mL ×
2), merge organic phase, wash (100mL × 3) with 10% sodium hydroxide solution, wash (100mL), nothing with saturated sodium chloride solution
Aqueous sodium persulfate dries, filters, and is concentrated to dryness, and obtains crude product, and with re crystallization from toluene, active carbon decoloring obtains yellow solid R- VII
9.4g, yield 79.3%, mp.71~73 DEG C.
Claims (10)
1. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, which comprises the following steps:
(1) synthesis of the bromo- 2- hydroxy-2-methyl propionic acid of (R) -3- and the bromo- 2- hydroxy-2-methyl propionic acid of (S) -3-
1. under alkaline condition, nucleophilic substitution occurs for D-PROLINE and methacrylic chloride in organic solvent, (2R)-is obtained
1- (2- methylacryloyl) nafoxidine -2- carboxylic acid (R- I)；Parent occurs for L-PROLINE and methacrylic chloride under similarity condition
Core substitution reaction obtains (2S) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid (R- I).
Bromination reaction occurs for (2. 2R) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid and bromide reagent, obtain (3R,
8R)-bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-II a of Isosorbide-5-Nitrae-diketone；
Bromination reaction occurs for (2S) -1- (2- methylacryloyl) nafoxidine -2- carboxylic acid and bromide reagent, obtains (3S, 8S) -
Bromomethyl -3- methyl nafoxidine simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-II b of Isosorbide-5-Nitrae-diketone.
3. simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-Isosorbide-5-Nitrae-diketone through sour water solution, obtains (3R, 8R)-bromomethyl -3- methyl nafoxidine
(R) the bromo- 2- hydroxy-2-methyl propionic acid (R- III) of -3-；
Simultaneously [2,1-c] [Isosorbide-5-Nitrae] oxazines-Isosorbide-5-Nitrae-diketone obtains (S) -3- through sour water solution to (3S, 8S)-bromomethyl -3- methyl nafoxidine
Bromo- 2- hydroxy-2-methyl propionic acid (S- III).
4. the bromo- 2- hydroxy-2-methyl propionic acid of (R) -3- and chlorination reagent act on, then exist with 4- cyano -3- 5-trifluoromethylaniline
Nucleophilic substitution occurs under the conditions of alkalinity and certain temperature, obtains the bromo- 2- hydroxy-2-methyl-N- of (R) -3- [(4- cyano -3- three
Methyl fluoride) phenyl] propionamide；
(S) the bromo- 2- hydroxy-2-methyl propionic acid of -3- and chlorination reagent act on, then with 4- cyano -3- 5-trifluoromethylaniline in alkali
Nucleophilic substitution occurs under the conditions of property and certain temperature, obtains the bromo- 2- hydroxy-2-methyl-N- of (S) -3- [(4- cyano -3- trifluoro
Methyl) phenyl] propionamide.
(2) (2S) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide and
The synthesis of (2R) -3- (4- cyano-benzene oxygen)-N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
Under base catalysis, in aprotic polar organic solvent, the bromo- 2- hydroxy-2-methyl-N- of (R) -3- [(4- cyano -3- trifluoro
Methyl) phenyl] nucleophilic substitution occurs for propionamide and 4-hydroxybenzonitrile, compound (2S) -3- (4- cyano-benzene oxygen)-is made
N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide (S-V)；
Under base catalysis, in aprotic polar organic solvent, the bromo- 2- hydroxy-2-methyl-N- of (S) -3- [(4- cyano -3- trifluoro
Methyl) phenyl] nucleophilic substitution occurs for propionamide and 4-hydroxybenzonitrile, compound (2R) -3- (4- cyano-benzene oxygen)-is made
N- [4- cyano -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide (R-V).
(3) (2S) -3- (4- acetoxyl group phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionyl
Amine and (2S) -3- (4- acetoxyl group phenoxy group)-N- [4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide
Synthesis
1. the bromo- 2- hydroxy-2-methyl propionic acid of (R) -3- is reacted with chlorination reagent, then sent out with 4- nitro-3-trifluoromethylaniline
Raw nucleophilic substitution, obtains the bromo- 2- hydroxy-2-methyl-N- of (R) -3- [(4- nitro -3- trifluoromethyl) phenyl] propionamide (R-
Ⅵ)；
(S) the bromo- 2- hydroxy-2-methyl propionic acid of -3- is reacted with chlorination reagent, is then occurred with 4- nitro-3-trifluoromethylaniline
Nucleophilic substitution obtains the bromo- 2- hydroxy-2-methyl-N- of (S) -3- [(4- nitro -3- trifluoromethyl) phenyl] propionamide (S-
Ⅵ)。
2. under phase transfer catalyst effect, the bromo- 2- hydroxy-2-methyl-N- of (R) -3- [(4- nitro -3- trifluoromethyl) phenyl]
With to acetaminophenol nucleophilic substitution occurs for propionamide, and compound (2S) -3- (4- acetoxyl group phenoxy group)-N- is made
[4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide (S- VII)；
Under phase transfer catalyst effect, the bromo- 2- hydroxy-2-methyl-N- of (S) -3- [(4- nitro -3- trifluoromethyl) phenyl] third
With to acetaminophenol nucleophilic substitution occurs for amide, and compound (2R) -3- (4- acetoxyl group phenoxy group)-N- is made
[4- nitro -3- trifluoromethyl] -2- hydroxy-2-methyl propionamide (R- VII).
The present invention is a kind of to efficiently synthesize optical activity alpha-hydroxypropanamide derivative method.
2. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In the alkaline condition is sodium hydroxide, potassium hydroxide, ammonium hydroxide, one of lithium hydroxide.
3. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In organic solvent is one of ketone and tetrahydrofuran mixed solvent, such as acetone, butanone, 2 pentanone of low molecular weight.
4. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In bromide reagent is the carbon tetrachloride solution of N- bromo-succinimide (NBS) or bromine.
5. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In acid used is sulfuric acid, hydrochloric acid, hydrobromic acid, preferably 24% hydrobromic acid.
6. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In chlorination reagent used is thionyl chloride, phosphorus trichloride and phosphorus pentachloride, preferably thionyl chloride.
7. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (1) exist according to claim 1
In alkali used is sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, N-methylcyclohexylamine, preferably triethylamine.Reaction temperature
Degree is preferably room temperature.
8. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (2) exist according to claim 1
In alkali used is sodium carbonate, potassium carbonate, triethylamine, diisopropylethylamine, N-methylcyclohexylamine, preferably potassium carbonate.
9. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (2) exist according to claim 1
In aprotic polar organic solvent used is n,N-Dimethylformamide or n,N-dimethylacetamide.
10. a kind of method of synthesizing optical active alpha-hydroxypropanamide derivative, feature described in (3) according to claim 1
It is, phase transfer catalyst is benzyl tributyl ammonium chloride, benzyl tributyl ammonium bromide, benzyltriethylammoinium chloride, benzyl three
Ethyl phosphonium bromide ammonium etc..It is preferred that benzyl tributyl ammonium chloride.
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| CN111646922B (en) * | 2020-07-21 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthetic method of 2- (4-bromo-2-cyano-6-fluorophenyl) acetic acid |
| CN112250599A (en) * | 2020-11-24 | 2021-01-22 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester |
| CN112250599B (en) * | 2020-11-24 | 2022-03-11 | 阿里生物新材料（常州）有限公司 | Synthesis method of 4-bromo-2-cyano-3-fluorobenzoic acid methyl ester |
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