CN103012350B - Synthetic method of benzopyran chiral compound - Google Patents
Synthetic method of benzopyran chiral compound Download PDFInfo
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- CN103012350B CN103012350B CN201210525326.7A CN201210525326A CN103012350B CN 103012350 B CN103012350 B CN 103012350B CN 201210525326 A CN201210525326 A CN 201210525326A CN 103012350 B CN103012350 B CN 103012350B
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 70
- KYNSBQPICQTCGU-UHFFFAOYSA-N Benzopyrane Chemical compound C1=CC=C2C=CCOC2=C1 KYNSBQPICQTCGU-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 238000010189 synthetic method Methods 0.000 title claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 32
- 239000000126 substance Substances 0.000 claims abstract description 31
- 239000000654 additive Substances 0.000 claims abstract description 28
- 230000000996 additive effect Effects 0.000 claims abstract description 28
- -1 benzoic acid compound Chemical class 0.000 claims abstract description 23
- 238000006482 condensation reaction Methods 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 90
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 42
- 235000002639 sodium chloride Nutrition 0.000 claims description 32
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 235000010290 biphenyl Nutrition 0.000 claims description 23
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 19
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 238000000605 extraction Methods 0.000 claims description 17
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- 239000002131 composite material Substances 0.000 claims description 16
- 239000012074 organic phase Substances 0.000 claims description 16
- HDMGAZBPFLDBCX-UHFFFAOYSA-M potassium;sulfooxy sulfate Chemical compound [K+].OS(=O)(=O)OOS([O-])(=O)=O HDMGAZBPFLDBCX-UHFFFAOYSA-M 0.000 claims description 16
- 150000003839 salts Chemical class 0.000 claims description 16
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- 239000011780 sodium chloride Substances 0.000 claims description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical group OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 claims description 7
- 235000015177 dried meat Nutrition 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 4
- 125000006267 biphenyl group Chemical group 0.000 claims description 4
- 230000000694 effects Effects 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical group C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 229910021529 ammonia Inorganic materials 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims 1
- 238000007254 oxidation reaction Methods 0.000 claims 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 230000003287 optical effect Effects 0.000 abstract description 2
- 239000005711 Benzoic acid Substances 0.000 abstract 2
- 235000010233 benzoic acid Nutrition 0.000 abstract 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 description 69
- 230000015572 biosynthetic process Effects 0.000 description 68
- 238000006243 chemical reaction Methods 0.000 description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 33
- 238000004440 column chromatography Methods 0.000 description 30
- 238000003756 stirring Methods 0.000 description 30
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- IAQRGUVFOMOMEM-UHFFFAOYSA-N butene Natural products CC=CC IAQRGUVFOMOMEM-UHFFFAOYSA-N 0.000 description 15
- 239000003814 drug Substances 0.000 description 14
- 229940079593 drug Drugs 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 0 *[C@]1OC2=C*(*)C=CC=C2C=C1C=O Chemical compound *[C@]1OC2=C*(*)C=CC=C2C=C1C=O 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- XUQMZWOYJJZSGD-SNVBAGLBSA-N (2R)-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound FC([C@@H]1OC2=CC=CC=C2C=C1C=O)(F)F XUQMZWOYJJZSGD-SNVBAGLBSA-N 0.000 description 3
- QSLSQLYQCKEGMS-SECBINFHSA-N (2R)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid Chemical compound FC([C@@H]1OC2=CC=CC=C2C=C1C(=O)O)(F)F QSLSQLYQCKEGMS-SECBINFHSA-N 0.000 description 3
- OXIOEYQBINWJJM-JTQLQIEISA-N (2S)-6-bromo-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound BrC=1C=C2C=C([C@H](OC2=CC=1)C(F)(F)F)C=O OXIOEYQBINWJJM-JTQLQIEISA-N 0.000 description 3
- MKKSTJKBKNCMRV-UHFFFAOYSA-N 5-bromo-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(Br)C=C1C=O MKKSTJKBKNCMRV-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- YNKMHABLMGIIFX-UHFFFAOYSA-N benzaldehyde;methane Chemical class C.O=CC1=CC=CC=C1 YNKMHABLMGIIFX-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- BDGYUXJRSNCKMT-LLVKDONJSA-N (2R)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound BrC=1C=C2C=C([C@@H](OC2=C(C=1)C)C(F)(F)F)C=O BDGYUXJRSNCKMT-LLVKDONJSA-N 0.000 description 2
- ILHUJLLYTPMLPK-SNVBAGLBSA-N (2R)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid Chemical compound CC1=CC(=CC2=C1O[C@H](C(=C2)C(=O)O)C(F)(F)F)Br ILHUJLLYTPMLPK-SNVBAGLBSA-N 0.000 description 2
- ZFKBWSREWJOSSJ-VIFPVBQESA-N (2s)-6,8-dichloro-2-(trifluoromethyl)-2h-chromene-3-carboxylic acid Chemical class ClC1=CC(Cl)=C2O[C@H](C(F)(F)F)C(C(=O)O)=CC2=C1 ZFKBWSREWJOSSJ-VIFPVBQESA-N 0.000 description 2
- OODLETPYKNYFPC-VIFPVBQESA-N (2s)-6-bromo-2-(trifluoromethyl)-2h-chromene-3-carboxylic acid Chemical compound BrC1=CC=C2O[C@H](C(F)(F)F)C(C(=O)O)=CC2=C1 OODLETPYKNYFPC-VIFPVBQESA-N 0.000 description 2
- UIFVCPMLQXKEEU-UHFFFAOYSA-N 2,3-dimethylbenzaldehyde Chemical class CC1=CC=CC(C=O)=C1C UIFVCPMLQXKEEU-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 description 2
- GFIMRXUUILBNOZ-SNVBAGLBSA-N (2R)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound C1=C(C=C(C2=C1C=C([C@@H](O2)C(F)(F)F)C=O)Cl)Cl GFIMRXUUILBNOZ-SNVBAGLBSA-N 0.000 description 1
- OXIOEYQBINWJJM-SNVBAGLBSA-N (2R)-6-bromo-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound BrC=1C=C2C=C([C@@H](OC2=CC=1)C(F)(F)F)C=O OXIOEYQBINWJJM-SNVBAGLBSA-N 0.000 description 1
- OODLETPYKNYFPC-SECBINFHSA-N (2R)-6-bromo-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid Chemical compound OC(=O)C1=Cc2cc(Br)ccc2O[C@H]1C(F)(F)F OODLETPYKNYFPC-SECBINFHSA-N 0.000 description 1
- GFIMRXUUILBNOZ-JTQLQIEISA-N (2S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound ClC=1C=C2C=C([C@H](OC2=C(C=1)Cl)C(F)(F)F)C=O GFIMRXUUILBNOZ-JTQLQIEISA-N 0.000 description 1
- BDGYUXJRSNCKMT-NSHDSACASA-N (2S)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound CC1=C2O[C@@H](C(C=O)=CC2=CC(Br)=C1)C(F)(F)F BDGYUXJRSNCKMT-NSHDSACASA-N 0.000 description 1
- ILHUJLLYTPMLPK-JTQLQIEISA-N (2S)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid Chemical compound BrC=1C=C2C=C([C@H](OC2=C(C1)C)C(F)(F)F)C(=O)O ILHUJLLYTPMLPK-JTQLQIEISA-N 0.000 description 1
- KFMMSNYBUGWUFK-JTQLQIEISA-N (2S)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound ClC=1C=C2C=C([C@H](OC2=CC=1)C(F)(F)F)C=O KFMMSNYBUGWUFK-JTQLQIEISA-N 0.000 description 1
- CRHAXIRNYGHVOU-NSHDSACASA-N (2S)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound CC=1C=C2C=C([C@H](OC2=CC=1)C(F)(F)F)C=O CRHAXIRNYGHVOU-NSHDSACASA-N 0.000 description 1
- SCHXYARCWXHADN-ZDUSSCGKSA-N (2S)-7-tert-butyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde Chemical compound C(C)(C)(C)C1=C(C=C2C=C([C@H](OC2=C1)C(F)(F)F)C=O)Cl SCHXYARCWXHADN-ZDUSSCGKSA-N 0.000 description 1
- ZFKBWSREWJOSSJ-SECBINFHSA-N (2r)-6,8-dichloro-2-(trifluoromethyl)-2h-chromene-3-carboxylic acid Chemical compound ClC1=CC(Cl)=C2O[C@@H](C(F)(F)F)C(C(=O)O)=CC2=C1 ZFKBWSREWJOSSJ-SECBINFHSA-N 0.000 description 1
- VEENGDJNDWZTOU-VIFPVBQESA-N (2s)-6-chloro-2-(trifluoromethyl)-2h-chromene-3-carboxylic acid Chemical compound ClC1=CC=C2O[C@H](C(F)(F)F)C(C(=O)O)=CC2=C1 VEENGDJNDWZTOU-VIFPVBQESA-N 0.000 description 1
- CAQAACVIDLCMLM-JTQLQIEISA-N (2s)-6-methyl-2-(trifluoromethyl)-2h-chromene-3-carboxylic acid Chemical compound O1[C@H](C(F)(F)F)C(C(O)=O)=CC2=CC(C)=CC=C21 CAQAACVIDLCMLM-JTQLQIEISA-N 0.000 description 1
- QGCKNIAMHUUUDI-LBPRGKRZSA-N (2s)-7-tert-butyl-6-chloro-2-(trifluoromethyl)-2h-chromene-3-carboxylic acid Chemical compound O1[C@H](C(F)(F)F)C(C(O)=O)=CC2=C1C=C(C(C)(C)C)C(Cl)=C2 QGCKNIAMHUUUDI-LBPRGKRZSA-N 0.000 description 1
- 235000001674 Agaricus brunnescens Nutrition 0.000 description 1
- JIQYFNLCBOEBSG-UHFFFAOYSA-N CCCCC1(C(=CC2=C(O1)C=CC(=C2)Cl)C(=O)O)C(F)(F)F Chemical group CCCCC1(C(=CC2=C(O1)C=CC(=C2)Cl)C(=O)O)C(F)(F)F JIQYFNLCBOEBSG-UHFFFAOYSA-N 0.000 description 1
- NONBXOPYDWLZGR-JTQLQIEISA-N Cc1cc(Cl)cc2c1O[C@H](C(F)(F)F)C(C(O)=O)=C2 Chemical compound Cc1cc(Cl)cc2c1O[C@H](C(F)(F)F)C(C(O)=O)=C2 NONBXOPYDWLZGR-JTQLQIEISA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000011914 asymmetric synthesis Methods 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 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
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 230000033912 thigmotaxis Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
Landscapes
- Pyrane Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a synthetic method of a benzopyran chiral compound. The method comprises the following steps: a compound with the structural formula I and a compound with the structural formula II carry out the condensation reaction to generate a compound with the structural formula III, and the compound with the structural formula III is oxidized to obtain the benzopyran chiral compound; the chemical additive adopts a benzoic acid or a substituted benzoic acid compound; and the chiral catalyst is a diphenyl prolinol ester compound or dinaphthyl prolinol ester compound. The synthetic method has the advantages that under the mild condition, relatively cheap raw materials are used, the benzopyran chiral compound derivate is synthesized with high yield, and the derivate is high in optical purity, accessible in raw material, and beneficial for large-scale production and application.
Description
Technical field
The invention belongs to chemical field, specifically relate to the synthetic method of a kind of benzo pyran chipal compounds and derivative thereof.
Background technology
Chirality is the essential characteristic of vital process, and the organic molecule overwhelming majority forming life entity is chiral molecules.The medicine overwhelming majority that people use has chirality, and be called as chiral drug, these chiral drugs have two enantiomers.Enantiomer is the spitting image of the right-hand man of people, and they seem closely similar, but incomplete same.When a chiral drug enters life entity, its two enantiomers can show different biological activitys usually.For chiral drug, an isomer may be effective, and another isomer may be invalid or even harmful.Chirality pharmacy is exactly this principle utilizing compound, develops the medicine that drug effect is high, side effect is little.In clinical treatment, the chiral drug taking enantiomer-pure not only can get rid of the toxic side effect caused by invalid (bad) enantiomorph, pharmaceutical quantities can also be reduced and human body is born the metabolism of invalid enantiomorph, there is better control to pharmacokinetics and dosage, improve the specificity of medicine.Thus there is very wide market outlook and huge economic worth.The total number of drugs used in the world is at present about 1900 kinds of chiral drugs and accounts for more than 50%, and in clinical 200 kinds of conventional medicines, chiral drug reaches 114 kinds.
Chiral drug generally obtains by extraction, racemate resolution method from natural product, in recent years, along with the development of synthesis method and the appearance of advanced analysis technology, increasing chipal compounds obtains asymmetric synthesis by chemical synthesis, and oneself becomes the important means obtaining chiral material.Synthesizing one of them enantiomorph by asymmetric reaction stereotaxis is obtain the most direct method of chiral drug.Chiral source synthesis is with natural chiral material for raw material, through the chiral material that the chemical reactive synthesis such as retention of configuration or configuration conversion is new.In chiral source synthesis, it must be all high selectivity that all synthesis change, and reacts chiral source molecular conversion the most at last become target chiral molecule by these.Carbohydrate, organic acid, amino acid, mushroom class chemical combination and alkaloid are very useful chiral synthesize starting raw materials, and can be used for complicated molecule complete synthesis in.
Existing benzo pyran chipal compounds, generally by Chiral Amine induced crystallization or utilize chiral column split obtain.Utilize the method for Chiral Amine induced crystallization, productive rate is generally lower, chiral resolving agent expensive.And utilizing chiral column to split, price is very expensive, is unfavorable for large-scale application.
Summary of the invention
The object of this invention is to provide the synthetic method of a kind of benzo pyran chipal compounds (comprising S configuration and R configuration).
Concrete technical scheme is as follows:
A kind of synthetic method of benzo pyran chipal compounds, in the environment of organic solvent and chemical additive, under chiral catalyst effect, the compound with structure shown in formula I and the compound generation condensation reaction with formula II structure generate the compound with formula III structure, the compound with formula III structure is oxidized, obtains target benzo pyran chipal compounds V; Described chemical additive is phenylformic acid or substituted benzoyl acid compounds; Described chiral catalyst is phenylbenzene dried meat ammonia estersil class or two how base dried meat ammonia silicon ester compound; Described have formula I, II, III, V structure compound as follows:
Wherein:
R
1one or morely to be selected from:
1) C
1~ C
10alkyl;
2) C
1~ C
10deuteroalkyl;
3) aryl;
4) C
1~ C
10aralkyl;
5) C
3~ C
8cycloalkyl;
6) heterocyclic radical;
7) C
3~ C
8halogenated cycloalkyl;
8) halogen;
9) C
1~ C
10haloalkyl;
10) halogenated aryl;
11) C
1~ C
10haloaralkyl;
R
2be selected from:
1) C
1~ C
10alkyl;
2) aryl;
3) C
1~ C
10aralkyl;
4) C
3~ C
8cycloalkyl;
5) heterocyclic radical;
6) C
3~ C
8halogenated cycloalkyl;
7) C
1~ C
10haloalkyl;
8) halogenated aryl;
9) C
1~ C
10haloaralkyl.
Wherein in some embodiments, described R
1for halogen, C
1~ C
10alkyl, C
1~ C
10deuteroalkyl, R
2for C
1~ C
10haloalkyl.
Wherein in some embodiments, described chiral catalyst is phenylbenzene dried meat ammonia silicon ester compound; Described chemical additive is substituted benzoyl acid compounds.
Wherein in some embodiments, described chiral catalyst is (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine, (2R)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine; Described chemical additive is p-nitrobenzoic acid or o-Carboxynitrobenzene.
Wherein in some embodiments, described organic solvent is chloroform, toluene, Virahol, ethyl acetate, Isosorbide-5-Nitrae-dioxane or acetonitrile.
Wherein in some embodiments, described organic solvent is ethyl acetate, chloroform.
Wherein in some embodiments, described condensation reaction is carried out under temperature is the condition of 20-100 DEG C; Reaction times is 8h-48h.
Wherein in some embodiments, described condensation reaction is carried out under temperature is the condition of 20-35 DEG C.
Wherein in some embodiments, the mol ratio of the compound of described structure shown in formula I and the compound of formula II structure is 1:2-3; The mol ratio of the compound of described chiral catalyst and structure shown in formula I is 1:4-6; The mol ratio of described chemical additive and chiral catalyst is 1-2:1.
Wherein in some embodiments, the mol ratio of the compound of described structure shown in formula I and the compound of formula II structure is 1:2; The mol ratio of the compound of described chiral catalyst and structure shown in formula I is 1:5; The mol ratio of described chemical additive and chiral catalyst is 1:1.
The synthetic method of benzo pyran chipal compounds of the present invention, tool has the following advantages: can be in a mild condition, use more cheap raw material, high productivity synthesis benzo pyran chipal compounds derivative, this derivative optical purity is high, raw material is easy to get, and is conducive to large-scale production application.
Embodiment
The present invention is understood further by following specific embodiment.
Embodiment 1
(S) synthesis of the chloro-2-trifluoromethyl of-7-tertiary butyl-6--2H-chromene-3-carboxylic acid
(S) the route of synthesis of-7-tertiary butyl-6-chloro-2-trifluoromethyl-2H-chromene-3-carboxylic acid is as follows:
Concrete steps are as follows:
Step 1:(S) synthesis of the chloro-2-trifluoromethyl of-7-tertiary butyl-6--2H-chromene-3-aldehyde
The compound 4-tertiary butyl-5-chlorine-2-hydroxyl phenyl aldehyde (1.0g of structure shown in formula I will be had, 4.7mmol), there is the compound 4 of formula II structure, 4,4-trifluoro but-2-ene aldehyde (1.16g, 9.4mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.31g, 0.94mmol), chemical additive p-nitrobenzoic acid (0.16g, 0.94mmol) is blended in 50mL ethyl acetate.This reaction solution stirs 24 hours at 25 DEG C, and after reaction terminates, column chromatography obtains the chloro-2-trifluoromethyl of product (the S)-7-tertiary butyl-6--2H-chromene-3-aldehyde (structure is as follows) 1.35g (yield is 90%).
(S) the chloro-2-trifluoromethyl of-7-tertiary butyl-6--2H-chromene-3-aldehyde
(S)-7-tert-butyl-6-chloro-2-(trifLuoromethyl)-2H-chromene-3-carbaldehyde
1HNMR(400MHz,CDCl3),δ9.67(s,1H),7.47(s,1H)，7.29(s,1H),7.10(s,1H),5.74(m,1H),1.49(s,9H)
Step 2:(S) synthesis of the chloro-2-trifluoromethyl of-7-tertiary butyl-6--2H-chromene-3-carboxylic acid
By above-mentioned product (1.35g, 4.2mmol) with potassium hydrogen persulfate composite salts (3.0g, 5.0mmol) be blended in the DMF of 30mL to stir and spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains the chloro-2-trifluoromethyl of product (the S)-7-tertiary butyl-6--2H-chromene-3-carboxylic acid (structure is as follows) 0.98g (yield is 70%).Analyze through chirality AD post, its EE value is higher than 92%.
(S) the chloro-2-trifluoromethyl of-7-tertiary butyl-6--2H-chromene-3-carboxylic acid
(S)-7-tert-butyl-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,CDCl3),δ7.78(s,1H),7.25(s,1H)，7.09(s,1H),5.72(m,1H),1.49(s,9H)
MS(MM-ES+APCI),m/z:334(M-1)
Embodiment 2
(S) chloro-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-) synthesis of-2H-chromene-3-carboxylic acid
(S) chloro-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-) route of synthesis of-2H-chromene-3-carboxylic acid is as follows:
Concrete steps are as follows:
Step 1:(S) chloro-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-) synthesis of-2H-chromene-3-aldehyde
Compound 3-chlorin-6-the hydroxyl-2 of structure shown in formula I will be had, deuterated dimethylbenzaldehyde (the 1.0g of 4-, 5.2mmol), there is the compound 4,4 of formula II structure, 4-trifluoro but-2-ene aldehyde (1.3g, 10.4mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.34g, 1.04mmol), chemical additive p-nitrobenzoic acid (0.34g, 2.08mmol) is blended in 50mL chloroform.This reaction solution stirs 48 hours at 25 DEG C, and after reaction terminates, column chromatography obtains chloro-5, the 7-deuterated dimethyl-2-(trifluoromethyls of product (S)-6-)-2H-chromene-3-aldehyde (structure is as follows) 1.2g (yield is 80%).
(S) chloro-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-)-2H-chromene-3-aldehyde
(S)-6-chloro-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
1HNMR(400MHz,CDCl3),δ9.73(s,1H),8.34(s,1H)，7.02(s,1H),5.99(m,1H)
Step 2:(S) chloro-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-) synthesis of-2H-chromene-3-carboxylic acid
By above-mentioned product (1.2g, 4.0mmol) with potassium hydrogen persulfate composite salts (2.7g, 4.4mmol) be blended in DMF(30mL) in stir spend the night, reaction terminate after, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, dry, vacuum rotary steam, column chromatography obtains chloro-5, the 7-deuterated dimethyl-2-(trifluoromethyls of product (S)-6-)-2H-chromene-3-carboxylic acid (structure is as follows) 0.81g (yield is 65%).
Analyze through chirality AD post, its EE value is higher than 90%.
(S) chloro-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-)-2H-chromene-3-carboxylic acid
(S)-6-chloro-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,CDCl3),δ8.09(s,1H),6.81(s,1H),5.68(m,1H)
MS(MM-ES+APCI),m/z:312(M–1)
Embodiment 3
(S) bromo-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-) synthesis of-2H-chromene-3-carboxylic acid
(S) bromo-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-) route of synthesis of-2H-chromene-3-carboxylic acid is as follows:
Concrete steps are as follows:
Step 1:(S) bromo-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-) synthesis of-2H-chromene-3-aldehyde
By the bromo-6-hydroxyl-2 of compound 3-with structure shown in formula I, deuterated dimethylbenzaldehyde (the 1.0g of 4-, 4.3mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.1g, 8.6mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.28g, 0.86mmol), chemical additive o-Carboxynitrobenzene (0.14g, 0.86mmol) being blended in 50mL chloroform. this reaction solution stirs 24 hours at 25 DEG C, after reaction terminates, column chromatography obtains product (S)-6-bromo-5, the deuterated dimethyl of 7--2-(trifluoromethyl)-2H-chromene-3-aldehyde (structure is as follows) 1.2g (yield is 80%).
(S) bromo-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-)-2H-chromene-3-aldehyde
(S)-6-bromo-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
1HNMR(400MHz,CDCl3),δ9.73(s,1H),8.35(s,1H)，7.03(s,1H),5.99(m,1H)
Step 2:(S) bromo-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-) synthesis of-2H-chromene-3-carboxylic acid
By above-mentioned product (1.2g, 3.5mmol) with potassium hydrogen persulfate composite salts (2.7g, 4.2mmol) be blended in DMF(30mL) in stir spend the night, reaction terminate after, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, dry, vacuum rotary steam, column chromatography obtains bromo-5, the 7-deuterated dimethyl-2-(trifluoromethyls of product (S)-6-)-2H-chromene-3-carboxylic acid (structure is as follows) 0.87g (yield is 70%).
Analyze through chirality AD post, its EE value is higher than 90%.
(S) bromo-5, the 7-deuterated dimethyl-2-(trifluoromethyls of-6-)-2H-chromene-3-carboxylic acid
(S)-6-bromo-5,7-(dimethyl-D6)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,CDCl3),δ8.09(s,1H),6.81(s,1H),5.68(m,1H)
MS(MM-ES+APCI),m/z:356(M-1)
Embodiment 4
(S) synthesis of the deuterated Methyl-2-trifluoromethyl of the chloro-8-of-6--2H-chromene-3-carboxylic acid
(S) route of synthesis of the deuterated Methyl-2-trifluoromethyl of the chloro-8-of-6--2H-chromene-3-carboxylic acid is as follows:
Step 1:(S) synthesis of the deuterated Methyl-2-trifluoromethyl of the chloro-8-of-6--2H-chromene-3-aldehyde
Deuterated tolyl aldehyde (the 1.0g of compound 5-chlorine-2-hydroxyl-4 of structure shown in formula I will be had, 5.7mmol), there is the compound 4 of formula II structure, 4,4-trifluoro but-2-ene aldehyde (1.4g, 11.4mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.36g, 1.1mmol), chemical additive o-Carboxynitrobenzene (0.18g, 1.1mmol) is blended in 50mL ethyl acetate.This reaction solution stirs 24 hours at 25 DEG C, and after reaction terminates, column chromatography obtains synthesis (structure the is as follows) 1.3g (yield is 80%) of the deuterated Methyl-2-trifluoromethyl of the chloro-8-of product (S)-6--2H-chromene-3-aldehyde.
(S) synthesis of the deuterated Methyl-2-trifluoromethyl of the chloro-8-of-6--2H-chromene-3-aldehyde
(S)-6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
1HNMR(400MHz,CDCl3),δ9.68(s,1H),8.47(s,1H)，7.38(s,1H),7.29(s,1H)，5.99(m,1H)
Step 2:(S) synthesis of the deuterated Methyl-2-trifluoromethyl of the chloro-8-of-6--2H-chromene-3-carboxylic acid
By above-mentioned product (1.3g, 4.6mmol) with potassium hydrogen persulfate composite salts (3.4g, 5.5mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains the deuterated Methyl-2-trifluoromethyl of the chloro-8-of product (S)-6--2H-chromene-3-carboxylic acid (structure is as follows) 0.96g (yield is 70%).Analyze through chirality AD post, its EE value is higher than 90%.
(S) the deuterated Methyl-2-trifluoromethyl of the chloro-8-of-6--2H-chromene-3-carboxylic acid
(S)-6-chloro-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,CDCl3),δ7.79(s,1H),7.21(s,1H),7.11(s,1H)，5.68(m,1H)
MS(MM-ES+APCI),m/z:295(M–1)
Embodiment 5
(S) synthesis of the deuterated Methyl-2-trifluoromethyl of the bromo-8-of-6--2H-chromene-3-carboxylic acid
(S) route of synthesis of the deuterated Methyl-2-trifluoromethyl of the bromo-8-of-6--2H-chromene-3-carboxylic acid is as follows:
Step 1:(S) synthesis of the deuterated Methyl-2-trifluoromethyl of the bromo-8-of-6--2H-chromene-3-aldehyde
Deuterated tolyl aldehyde (the 1.0g of compound 5-bromo-2-hydroxyl-4 of structure shown in formula I will be had, 4.6mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.1g, 9.2mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.30g, 0.92mmol), chemical additive p-nitrobenzoic acid (0.15g, 0.92mmol) be blended in 50mL ethyl acetate, this reaction solution stirs 24 hours at 25 DEG C, after reaction terminates, column chromatography obtains the deuterated Methyl-2-trifluoromethyl of the bromo-8-of product (S)-6--2H-chromene-3-aldehyde (structure is as follows) 1.2g (yield is 80%).
(S) the deuterated Methyl-2-trifluoromethyl of the bromo-8-of-6--2H-chromene-3-aldehyde
(S)-6-bromo-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
1HNMR(400MHz,CDCl3),δ9.68(s,1H),8.47(s,1H)，7.38(s,1H),7.29(s,1H)，5.99(m,1H)
Step 2:(S) synthesis of the deuterated Methyl-2-trifluoromethyl of the bromo-8-of-6--2H-chromene-3-carboxylic acid
By above-mentioned product (1.2g, 3.7mmol) with potassium hydrogen persulfate composite salts (2.7g, 4.4mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains the deuterated Methyl-2-trifluoromethyl of the bromo-8-of product (S)-6--2H-chromene-3-carboxylic acid (structure is as follows) 0.82g (yield is 65%).Analyze through chirality AD post, its EE value is higher than 90%.
(S) the deuterated Methyl-2-trifluoromethyl of the bromo-8-of-6--2H-chromene-3-carboxylic acid
(S)-6-bromo-8-(methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,CDCl3),δ7.79(s,1H),7.21(s,1H),7.11(s,1H)，5.68(m,1H)
MS(MM-ES+APCI),m/z:339(M-1)
Embodiment 6
(S) synthesis of the deuterated methyl of the chloro-6-of-8--2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(S) route of synthesis of the deuterated methyl of the chloro-6-of-8--2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid is as follows:
Step 1:(s) synthesis of the deuterated methyl of the chloro-6-of-8--2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
Deuterated tolyl aldehyde (the 1.0g of compound 3-chlorin-2-hydroxyl-5-of structure shown in formula I will be had, 5.7mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.4g, 11.4mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.36g, 1.1mmol), chemical additive p-nitrobenzoic acid (0.18g, 1.1mmol) be blended in 50mL ethyl acetate, this reaction solution stirs 24 hours at 25 DEG C, after reaction terminates, column chromatography obtains the deuterated methyl of the chloro-6-of product (s)-8--2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde (structure is as follows) 0.96g (yield is 60%).
The deuterated methyl of the chloro-6-of (s)-8--2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
(S)-8-chloro-(6-methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
MS(MM-ES+APCI),m/z:279(M-1)
Step 2.:(S) synthesis of the deuterated methyl of the chloro-6-of-8--2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
By above-mentioned product (0.96g, 3.4mmol) with potassium hydrogen persulfate composite salts (2.5g, 4.0mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains the deuterated methyl of the chloro-6-of product (s)-8--2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid (structure is as follows) 0.5g (yield is 50%).Analyze through chirality AD post, its EE value is higher than 90%.
The deuterated methyl of the chloro-6-of (s)-8--2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(s)-8-chloro-(6-methyl-D3)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ7.83(s,1H),7.34(s,1H),7.27(s,1H)，6.04(m,1H)
MS(MM-ES+APCI),m/z:295(M–1)
Embodiment 7
(S) synthesis of-6-methyl-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(S) route of synthesis of-6-methyl-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid is as follows:
Step 1:(S) synthesis of-6-methyl-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
The compound 5-cresotinic acid aldehyde (1.0g of structure shown in formula I will be had, 7.4mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.8g, 14.8mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.49g, 1.5mmol), chemical additive p-nitrobenzoic acid (0.25g, 1.5mmol) be blended in 50mL ethyl acetate, this reaction solution stirs 48 hours at 25 DEG C, after reaction terminates, column chromatography obtains product (S)-6-methyl-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde (structure is as follows) 1.5g (yield is 85%).
(S)-6-methyl-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
(S)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
MS(MM-ES+APCI),m/z:241(M–1)
Step 2:(S) synthesis of-6-methyl-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
By above-mentioned product (1.5g, 6.2mmol) with potassium hydrogen persulfate composite salts (4.6g, 7.4mmol) be blended in DMF(40mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains product (s)-6-methyl-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid (structure is as follows) 1.0g (yield is 65%).Analyze through chirality AD post, its EE value is higher than 92%.
(S)-6-methyl-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(S)-6-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ7.80(s,1H),7.28(s,1H),7.19(d,1H)，6.91(d,1H),5.86(m,1H)
MS(MM-ES+APCI),m/z:257(M–1)
Embodiment 8
(S) the chloro-8-methyl of-6--2-(trifluoromethyl) synthesis of-2H-chromene-3-carboxylic acid
(S)-6-chloro-8-methyl-2-(trifluoromethyl) route of synthesis of-2H-chromene-3-carboxylic acid is as follows:
Step 1:(S) the chloro-8-methyl of-6--2-(trifluoromethyl) synthesis of-2H-chromene-3-aldehyde
The compound 5-chloro-2-methyl salicylic aldehyde (1.0g of structure shown in formula I will be had, 5.8mmol), there is the compound 4 of formula II structure, 4,4-trifluoro but-2-ene aldehyde (1.44g, 11.6mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.39g, 1.2mmol), chemical additive o-Carboxynitrobenzene (0.20g, 1.2mmol) is blended in 50mL ethyl acetate.This reaction solution stirs 24 hours at 25 DEG C, and after reaction terminates, column chromatography obtains the chloro-8-methyl of product (s)-6--2-(trifluoromethyl)-2H-chromene-3-aldehyde (structure is as follows) 1.3g (yield is 80%).
(S) the chloro-8-methyl of-6--2-(trifluoromethyl)-2H-chromene-3-aldehyde
(S)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
1HNMR(400MHz,CDCl3),δ9.68(s,1H),7.50(s,1H),7.28(s,1H)，7.03(s,1H),5.82(m,1H)
MS(MM-ES+APCI),m/z:276(M–1)
Step 2:(S) the chloro-8-methyl of-6--2-(trifluoromethyl) synthesis of-2H-chromene-3-carboxylic acid
By above-mentioned product (1.3g, 4.7mmol) with potassium hydrogen persulfate composite salts (3.5g, 5.6mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains the chloro-8-methyl of product (S)-6--2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (structure is as follows) 0.96g (yield is 70%).Analyze through chirality AD post, its EE value is higher than 92%.
(S) the chloro-8-methyl of-6--2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
(S)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,CDCl3),δ7.81(s,1H),7.25(s,1H),6.99(s,1H)，5.81(m,1H)
MS(MM-ES+APCI),m/z:292(M-1)
Embodiment 9
(S) synthesis of the chloro-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(S) synthesis of the chloro-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid is by way of as follows:
Step 1:(S) synthesis of the chloro-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
The compound 5-chloro-salicylic aldehyde (1.0g of structure shown in formula I will be had, 6.37mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.6g, 12.7mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.41g, 1.27mmol), chemical additive p-nitrobenzoic acid (0.21g, 1.27mmol) be blended in 50mL ethyl acetate, this reaction solution stirs 24 hours at 25 DEG C, after reaction terminates, column chromatography obtains the chloro-2-of product (s)-6-(trifluoromethyl)-2H--2H-chromene-3-aldehyde (structure is as follows) 1.3g (yield is 75%).
(S) the chloro-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
(S)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
MS(MM-ES+APCI),m/z:262(M-1)
Step 2:(S) synthesis of the chloro-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
By above-mentioned product (1.3g, 4.9mmol) with potassium hydrogen persulfate composite salts (3.6g, 5.9mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains product (S)-6-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid (structure is as follows) 0.68g (yield is 50%).Analyze through chirality AD post, its EE value is higher than 92%.
(S) the chloro-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(S)-6-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ7.87(s,1H),7.64(s,1H),7.43(d,1H)，7.06(d,1H),5.97(m,1H)
MS(MM-ES+APCI),m/z:278(M–1)
Embodiment 10
(S)-6,8-bis-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acids
(S) route of synthesis of-6,8-bis-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acids is as follows:
Step 1:(s) synthesis of-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
The compound 3 of structure shown in formula I will be had, 5-dichloro-salicylaldehyde (1.0g, 5.23mmol), there is the compound 4,4 of formula II structure, 4-trifluoro but-2-ene aldehyde (1.3g, 10.4mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.34g, 1.04mmol), chemical additive o-Carboxynitrobenzene (0.17g, 1.04mmol) is blended in 50mL chloroform.This reaction solution stirs 8 hours at 25 DEG C, and after reaction terminates, column chromatography obtains product (s)-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde (structure is as follows) 1.0g (yield is 65%).
(S)-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
MS(MM-ES+APCI),m/z:296(M–1)
Step 2:(s) synthesis of-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acids
By above-mentioned product (1.0g, 3.4mmol) with potassium hydrogen persulfate composite salts (2.5g, 4.0mmol) be blended in DMF(30mL) in stir spend the night, reaction terminate after, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, dry, vacuum rotary steam, column chromatography obtains product (S)-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid (structure is as follows) 0.48g (yield is 45%).Analyze through chirality AD post, its EE value is higher than 92%.
(S)-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acids
(S)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ7.90(s,1H),7.72(s,1H),7.66(s,1H)，6.18(m,1H),
MS(MM-ES+APCI),m/z:312(M–1)
Embodiment 11
(S) synthesis of the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(S) route of synthesis of the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid is as follows:
Step 1:(S) synthesis of the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
The compound 5-bromosalicylaldehyde (1.0g of structure shown in formula I will be had, 5.0mmol), there is the compound 4 of formula II structure, 4,4-trifluoro but-2-ene aldehyde (1.2g, 10.0mmol), chiral catalyst (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.33g, 1.0mmol), chemical additive o-Carboxynitrobenzene (0.17g, 1.0mmol) is blended in 50mL ethyl acetate.This reaction solution stirs 24 hours at 25 DEG C, and after reaction terminates, column chromatography obtains product (S)-6-bromo-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde (structure is as follows) 1.0g (yield is 70%).
(S) the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
(S)-6-bromo-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
MS(MM-ES+APCI),m/z:306(M–1)
Step 2:(s) synthesis of the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
By above-mentioned product (1.0g, 3.3mmol) with potassium hydrogen persulfate composite salts (2.4g, 3.9mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains product (S)-6-bromo-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid (structure is as follows) 0.43g (yield is 40%).Analyze through chirality AD post, its EE value is higher than 92%.
(S) the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(S)-6-bromo-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ7.87(s,1H),7.64(s,1H),7.43(d,1H)，7.06(d,1H),5.99(m,1H)
MS(MM-ES+APCI),m/z:322(M-1)
Embodiment 12
(R) synthesis of the bromo-8-methyl of-6--2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
(R) route of synthesis of-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid is as follows:
Step 1:(R) the bromo-8-methyl of-6---the synthesis of 2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
The compound 5-bromo-2-hydroxy-3-methyl phenyl aldehyde (1.12g of structure shown in formula I will be had, 5.23mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.3g, 10.4mmol), chiral catalyst (2R)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.34g, 1.04mmol), chemical additive p-nitrobenzoic acid (0.17g, 1.04mmol) be blended in 50mL chloroform, this reaction solution stirs 24 hours at 25 DEG C, after reaction terminates, column chromatography obtains the bromo-8-methyl of product (R)-6---2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde (structure is as follows) 1.3g (yield is 77%).
(R) the bromo-8-methyl of-6---2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
(R)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
1HNMR(400MHz,DMSO),δ9.68(s,1H),7.99(s,1H),7.62(s,1H),7.56(s,1H),6.06(m,1H),2.18(s,3H),
MS(MM-ES+APCI),m/z:320(M-1)
Step 2:(R) synthesis of the bromo-8-methyl of-6--2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
By above-mentioned product (1.09g, 3.4mmol) with potassium hydrogen persulfate composite salts (2.5g, 4.0mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains the bromo-8-methyl of product (R)-6--2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (structure is as follows) 0.48g (yield is 45%).Analyze through chirality AD post, its EE value is higher than 87.5%.
(R) the bromo-8-methyl of-6--2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
(R)-6-bromo-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ13.40(s,1H),7.83(s,1H),7.58(s,1H),7.48(s,1H)，5.99(m,1H),2.17(s,3H),
MS(MM-ES+APCI),m/z:336(M–1)
Embodiment 13
(R) synthesis of-6,8-bis-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acids
(R) synthesis of-6,8-bis-chloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acids is by way of as follows:
Step 1:(R) synthesis of-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
The compound 3 of structure shown in formula I will be had, 5-dichloro-salicylaldehyde (1.0g, 5.23mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.3g, 10.4mmol), chiral catalyst (2R)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.34g, 1.04mmol), chemical additive p-nitrobenzoic acid (0.17g, 1.04mmol) be blended in stirring at room temperature 24h in 50mL ethyl acetate, after reaction terminates, column chromatography obtains product (R)-6, the chloro-2-of 8-bis-(trifluoromethyl)-2H--2H-chromene-3-aldehyde (structure is as follows) 0.9g (yield is 58%).
(R)-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
(R)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
MS(MM-ES+APCI),m/z:296(M–1)
Step 2:(R) synthesis of-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acids
By above-mentioned product (1.0g, 3.4mmol) with potassium hydrogen persulfate composite salts (2.5g, 4.0mmol) be blended in DMF(30mL) in stir spend the night, reaction terminate after, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, dry, vacuum rotary steam, column chromatography obtains product (R)-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid (structure is as follows) 0.48g (yield is 45%).Analyze through chirality AD post, its EE value is higher than 92%.
(R)-6,8-bis-chloro-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acids
(R)-6,8-dichloro-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ7.90(s,1H),7.72(s,1H),7.66(s,1H)，6.18(m,1H),
MS(MM-ES+APCI),m/z:312(M–1)
Embodiment 14
(R) synthesis of the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(R) synthesis of the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid is by way of as follows:
Step 1:(R) synthesis of the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
The compound 5-bromosalicylaldehyde (1.0g of structure shown in formula I will be had, 5.0mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.2g, 10.0mmol), chiral catalyst (2R)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.33g, 1.0mmol), chemical additive p-nitrobenzoic acid (0.17g, 1.0mmol) be blended in stirring at room temperature 48h in 50mL ethyl acetate, after reaction terminates, column chromatography obtains product (R)-6-bromo-2-(trifluoromethyl)-2H--2H-chromene-3-aldehyde (structure is as follows) 1.0g (yield is 70%).
(R) the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-aldehyde
(R)-6-bromo-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
1HNMR(400MHz,DMSO),δ9.69(s,1H),8.02(s,1H),7.80(s,1H),7.62(d,1H),7.02(d,1H),6.03(m,1H),
MS(MM-ES+APCI),m/z:306(M–1)
The synthesis of step 2. (R)-6-bromo-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
By above-mentioned product (1.0g, 3.3mmol) with potassium hydrogen persulfate composite salts (2.4g, 3.9mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains product (R)-6-bromo-2-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid (structure is as follows) 0.43g (yield is 40%).Analyze through chirality AD post, its EE value is higher than 85%.
(R) the bromo-2-of-6-(trifluoromethyl)-2H--2H-chromene-3-carboxylic acid
(R)-6-bromo-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ7.87(s,1H),7.75(s,1H),7.54(d,1H)，7.02(d,1H),5.99(m,1H)
MS(MM-ES+APCI),m/z:322(M-1)
Embodiment 15
(R) synthesis of-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
(R) route of synthesis of-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid is as follows:
Step 1:(R) synthesis of-2-(trifluoromethyl)-2H-chromene-3-aldehyde
(R) synthesis of-2-(trifluoromethyl)-2H-chromene-3-aldehyde is by way of as follows:
Compound salicylic aldehyde (the 0.61g of structure shown in formula I will be had, 5.0mmol), there is the compound 4 of formula II structure, 4, 4-trifluoro but-2-ene aldehyde (1.2g, 10.0mmol), chiral catalyst (2R)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine (0.33g, 1.0mmol), chemical additive p-nitrobenzoic acid (0.17g, 1.0mmol) be blended in stirring at room temperature 48h in 50mL ethyl acetate, after reaction terminates, column chromatography obtains product (R)-2-(trifluoromethyl)-2H-chromene-3-aldehyde (structure is as follows) 0.8g (yield is 70%).
(R)-2-(trifluoromethyl)-2H-chromene-3-aldehyde
(R)-2-(trifluoromethyl)-2H-chromene-3-carbaldehyde
MS(MM-ES+APCI),m/z:227(M-1)
Step 2:(R) synthesis of-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
By above-mentioned product (0.75g, 3.3mmol) with potassium hydrogen persulfate composite salts (2.4g, 3.9mmol) be blended in DMF(30mL) in stir spend the night, after reaction terminates, add water, be extracted with ethyl acetate, extraction gained organic phase saturated aqueous common salt is washed, drying, vacuum rotary steam, column chromatography obtains product (R)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (structure is as follows) 0.32g (yield is 40%).Analyze through chirality AD post, its EE value is higher than 92%.
(R)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
(R)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid
1HNMR(400MHz,DMSO),δ7.86(s,1H),7.48(d,1H),7.38(t,1H),7.05(m,2H),5.91(m,1H),
MS(MM-ES+APCI),m/z:243(M–1)
The above embodiment only have expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but therefore can not be interpreted as the restriction to the scope of the claims of the present invention.It should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (6)
1. the synthetic method of a benzo pyran chipal compounds, it is characterized in that, in the environment of organic solvent and chemical additive, under chiral catalyst effect, the compound with structure shown in formula I and the compound generation condensation reaction with formula II structure generate the compound with formula III structure, the compound with formula III structure is oxidized, obtains target benzo pyran chipal compounds V; Described chemical additive is phenylformic acid or substituted benzoyl acid compounds; Described chiral catalyst is phenylbenzene dried meat ammonia estersil class or two how base dried meat ammonia silicon ester compound; Described have formula I, II, III, V structure compound as follows:
Wherein:
R
1one or morely to be selected from:
1) C
1~ C
10alkyl;
2) C
1~ C
10deuteroalkyl;
3) halogen;
R
2be selected from:
Trifluoromethyl;
Described organic solvent is ethyl acetate or chloroform;
The mol ratio of the compound of described structure shown in formula I and the compound of formula II structure is 1:2-3; The mol ratio of the compound of described chiral catalyst and structure shown in formula I is 1:4-6; The mol ratio of described chemical additive and chiral catalyst is 1-2:1;
The method of described oxidation is: the compound and potassium hydrogen persulfate composite salts with formula III structure are blended in DMF solution and react, add water, be extracted with ethyl acetate, and extraction gained organic phase saturated aqueous common salt is washed, dry, vacuum rotary steam.
2. synthetic method according to claim 1, is characterized in that, described chiral catalyst is phenylbenzene dried meat ammonia silicon ester compound; Described chemical additive is substituted benzoyl acid compounds.
3. synthetic method according to claim 2, it is characterized in that, described chiral catalyst is (2S)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine, (2R)-2-[phenylbenzene [(trimethylsilyl group) oxygen base] methyl]-tetramethyleneimine; Described chemical additive is p-nitrobenzoic acid or o-Carboxynitrobenzene.
4. synthetic method according to claim 1, is characterized in that, described condensation reaction is carried out under temperature is the condition of 20-100 DEG C; Reaction times is 8h-48h.
5. synthetic method according to claim 4, is characterized in that, described condensation reaction is carried out under temperature is the condition of 20-35 DEG C.
6. synthetic method according to claim 1, is characterized in that, the mol ratio of the compound of described structure shown in formula I and the compound of formula II structure is 1:2; The mol ratio of the compound of described chiral catalyst and structure shown in formula I is 1:5; The mol ratio of described chemical additive and chiral catalyst is 1:1.
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| EP3094333B1 (en) * | 2014-01-14 | 2020-10-14 | Euclises Pharmaceuticals, Inc. | No-releasing nitrooxy-chromene conjugates |
| US11555023B2 (en) | 2019-01-22 | 2023-01-17 | Askat Inc. | Process for the differential solubility-driven asymmetric transformation of substituted 2H-chromene-3-carboxylic acids |
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