CN110938028A - Preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole - Google Patents
Preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 41
- KTUCROBKAQWWPX-ZCFIWIBFSA-N (1r)-5-bromo-1-methyl-2,3-dihydro-1h-isoindole Chemical compound BrC1=CC=C2[C@@H](C)NCC2=C1 KTUCROBKAQWWPX-ZCFIWIBFSA-N 0.000 title claims abstract description 33
- 239000007795 chemical reaction product Substances 0.000 claims abstract description 50
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 29
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 claims abstract description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 20
- 239000001257 hydrogen Substances 0.000 claims abstract description 20
- SUISZCALMBHJQX-UHFFFAOYSA-N 3-bromobenzaldehyde Chemical compound BrC1=CC=CC(C=O)=C1 SUISZCALMBHJQX-UHFFFAOYSA-N 0.000 claims abstract description 18
- 239000002904 solvent Substances 0.000 claims abstract description 18
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims abstract description 14
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 14
- 239000003054 catalyst Substances 0.000 claims abstract description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000010992 reflux Methods 0.000 claims abstract description 12
- 239000007787 solid Substances 0.000 claims abstract description 12
- 238000003756 stirring Methods 0.000 claims abstract description 12
- 238000000967 suction filtration Methods 0.000 claims abstract description 12
- 238000001816 cooling Methods 0.000 claims abstract description 8
- 238000010438 heat treatment Methods 0.000 claims abstract description 8
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 6
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 6
- 239000007864 aqueous solution Substances 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 4
- 238000001953 recrystallisation Methods 0.000 claims abstract description 4
- 238000005406 washing Methods 0.000 claims abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- 238000006243 chemical reaction Methods 0.000 claims description 38
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 36
- 238000000034 method Methods 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 239000007789 gas Substances 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 6
- 239000001358 L(+)-tartaric acid Substances 0.000 claims description 6
- 235000011002 L(+)-tartaric acid Nutrition 0.000 claims description 6
- FEWJPZIEWOKRBE-LWMBPPNESA-N L-(+)-Tartaric acid Natural products OC(=O)[C@@H](O)[C@H](O)C(O)=O FEWJPZIEWOKRBE-LWMBPPNESA-N 0.000 claims description 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 6
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- COFMBBYARPOGBA-UHFFFAOYSA-N 1-phenylethanesulfonic acid Chemical compound OS(=O)(=O)C(C)C1=CC=CC=C1 COFMBBYARPOGBA-UHFFFAOYSA-N 0.000 claims description 2
- CMIBUZBMZCBCAT-UHFFFAOYSA-N 2,3-bis[(4-methylbenzoyl)oxy]butanedioic acid Chemical compound C1=CC(C)=CC=C1C(=O)OC(C(O)=O)C(C(O)=O)OC(=O)C1=CC=C(C)C=C1 CMIBUZBMZCBCAT-UHFFFAOYSA-N 0.000 claims description 2
- -1 L- (+) -glycine Chemical compound 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 2
- FKCBLVCOSCZFHV-UHFFFAOYSA-N acetonitrile;ethanol Chemical compound CCO.CC#N FKCBLVCOSCZFHV-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 2
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229910052763 palladium Inorganic materials 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 24
- 239000000047 product Substances 0.000 abstract description 8
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 64
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- SUYJXERPRICYRX-UHFFFAOYSA-N (3-bromophenyl)methanamine Chemical compound NCC1=CC=CC(Br)=C1 SUYJXERPRICYRX-UHFFFAOYSA-N 0.000 description 16
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000006467 substitution reaction Methods 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 8
- 238000005984 hydrogenation reaction Methods 0.000 description 8
- 230000035484 reaction time Effects 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 7
- 238000011534 incubation Methods 0.000 description 7
- 230000000694 effects Effects 0.000 description 6
- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 description 5
- 238000013461 design Methods 0.000 description 5
- 229960003923 gatifloxacin Drugs 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 239000003344 environmental pollutant Substances 0.000 description 2
- 229940124307 fluoroquinolone Drugs 0.000 description 2
- 231100000719 pollutant Toxicity 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- LIBZHYLTOAGURM-UHFFFAOYSA-N 1-(3-bromophenyl)ethanamine Chemical compound CC(N)C1=CC=CC(Br)=C1 LIBZHYLTOAGURM-UHFFFAOYSA-N 0.000 description 1
- WYECURVXVYPVAT-UHFFFAOYSA-N 1-(4-bromophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Br)C=C1 WYECURVXVYPVAT-UHFFFAOYSA-N 0.000 description 1
- ZSZCXAOQVBEPME-UHFFFAOYSA-N 2-(4-bromophenyl)ethanamine Chemical compound NCCC1=CC=C(Br)C=C1 ZSZCXAOQVBEPME-UHFFFAOYSA-N 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- LGRFSURHDFAFJT-UHFFFAOYSA-N Phthalic anhydride Natural products C1=CC=C2C(=O)OC(=O)C2=C1 LGRFSURHDFAFJT-UHFFFAOYSA-N 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 206010070863 Toxicity to various agents Diseases 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- JHIWVOJDXOSYLW-UHFFFAOYSA-N butyl 2,2-difluorocyclopropane-1-carboxylate Chemical compound CCCCOC(=O)C1CC1(F)F JHIWVOJDXOSYLW-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- DKJXHDWXPQAPDW-SECBINFHSA-N tert-butyl (1R)-5-bromo-1-methyl-1,3-dihydroisoindole-2-carboxylate Chemical compound BrC=1C=C2CN([C@@H](C2=CC=1)C)C(=O)OC(C)(C)C DKJXHDWXPQAPDW-SECBINFHSA-N 0.000 description 1
- 229960000497 trovafloxacin Drugs 0.000 description 1
- WVPSKSLAZQPAKQ-CDMJZVDBSA-N trovafloxacin Chemical compound C([C@H]1[C@@H]([C@H]1C1)N)N1C(C(=CC=1C(=O)C(C(O)=O)=C2)F)=NC=1N2C1=CC=C(F)C=C1F WVPSKSLAZQPAKQ-CDMJZVDBSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Indole Compounds (AREA)
Abstract
The invention discloses a preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, which comprises the following steps: dissolving 3-bromobenzaldehyde in a first solvent, adding ammonia water and a catalyst, reacting in a hydrogen atmosphere, filtering, and concentrating to obtain a first reaction product; dissolving the first reaction product in a second solvent, cooling to-20 ℃, dropwise adding inorganic acid, adding an acetaldehyde aqueous solution, heating to a reflux temperature, reacting for 5-15 h, then concentrating under reduced pressure to 1/3 volume, adjusting the pH to 9-10, stirring overnight, performing suction filtration and recrystallization to obtain a second reaction product; dissolving the second reaction product in a third solvent, dropwise adding a resolving agent, then preserving heat at 40-80 ℃ for 1-7 h, concentrating under reduced pressure to 1/2 volume, stirring overnight at room temperature, carrying out suction filtration and washing, adding the obtained solid into water, slightly heating for dissolving, then adjusting pH to 9-10, cooling to 10 ℃, stirring overnight, and carrying out suction filtration to obtain the target product. The preparation method provided by the invention is simple to operate, the raw materials are easy to obtain, the cost is saved, and the preparation method is suitable for industrial production.
Description
Technical Field
The invention relates to the technical field of synthesis of organic intermediates, in particular to a preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole.
Background
Garafloxacin is a new quinolone drug developed by fushan corporation of japan (Toyama) together with the great positive pharmaceutical industry, and was approved for sale in japan in 2007. The gatifloxacin is mainly used for treating respiratory tract and otorhinolaryngological infection, has stronger activity on multi-drug resistant streptococcus pneumoniae, and has higher activity than that of ciprofloxacin and trovafloxacin. Unlike previous fluoroquinolone drugs, removal of fluorine at the 6-position of the quinolone mother nucleus of gatifloxacin not only improves activity but also reduces drug toxicity. Therefore, the market of the gatifloxacin has the potential to eliminate the shadow that the fluoroquinolone product is covered in the heart of people because of the serious side effect problem.
The (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole is an important intermediate of the gatifloxacin, and the cost of the intermediate greatly influences the raw material cost of the gatifloxacin. Currently, the following methods are available for the synthesis of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole:
1. the publication number is: CN106957255A, a Chinese patent of the invention, discloses (R) -N-Boc-5-bromo-1-methylisoindoline and a preparation method thereof, wherein the method takes p-bromoacetophenone as a raw material. The route is seemingly simple, but the bromoacetophenone as the raw material needs to be synthesized by itself, and from the actual repeated result, the reaction system is messy, and the product is difficult to separate.
And the products in the ring-closure step are mostly
The specific reaction equation is as follows:
2. the literature (Organic Letters,2018, vol.20, #9, p.2595-2598) discloses a preparation method using 3-bromo-1-phenylethylamine as a raw material. The raw materials of the route are synthesized by self, the reaction conditions are harsh, and special equipment is needed. We have verified that about 12 times the molar amount of sodium borohydride is required in the reduction step and the raw material cost is too high. The specific reaction equation is as follows:
3. the literature (WO 2014/146490; Synthetic Communications,2004, vol.34, #5, p.853-861; Tetrahedron Letters,2002, vol.43, #50, p.9163-9165) discloses a preparation method of taking phthalic anhydride as a raw material and obtaining a target product through resolution. The method has the advantages of high price of reagents, large dosage, a plurality of byproducts in the bromination step and difficult separation. The same is too costly in the sodium borohydride reduction step. The specific reaction equation is as follows:
4. for example, the p-bromophenylethylamine is used as a raw material, and the target product is obtained by splitting the raw material. The method has multiple reaction steps, harsh conditions and expensive reagents. The specific reaction equation is as follows:
5. the publication number is: U.S. patent 2002/173517 discloses a process for the preparation of polybrominated starting materials which is difficult to prepare. The specific reaction equation is as follows:
6. international application patents with publication numbers WO2015/150565 and WO2017/68412 disclose a method for obtaining a target product by using 6-bromoisoindoline-1-ketone as a starting material and then resolving. The method has the advantages of easily available raw materials, complex operation process, strict water control requirement, expensive reagent and high raw material cost. The specific reaction equation is as follows:
therefore, it is clear that the above-mentioned conventional preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole still has inconvenience and drawbacks in method and use, and further improvement is needed. In order to solve the problems of the preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, relevant manufacturers have no thought to solve the problems, but no suitable design has been developed for a long time, and no appropriate method can solve the problems in the general method, which is obviously a problem to be solved by the relevant manufacturers.
In view of the above-mentioned drawbacks of the conventional preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the present inventors have conducted extensive practical experience and professional knowledge for many years in the design and manufacture of such products, and have conducted active research and innovation in combination with the application of theories, in order to create a novel preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, which can improve the conventional preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, and thus make it more practical. After continuous research and design and repeated trial and improvement, the invention with practical value is finally created.
Disclosure of Invention
The invention mainly aims to overcome the defects of the existing preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, and provides a novel preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, which can effectively solve the problems of difficult obtainment of raw materials, high price, complex preparation method, harsh reaction conditions and high cost in the existing preparation method. The preparation method disclosed has mild conditions, high yield of each step, less waste of raw materials and reagents, less three wastes and environmental friendliness; the raw materials are easy to obtain and stable in supply, the cost is low, and the prepared (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole has the advantages of high purity and high yield, so that the method is more practical and has industrial utilization value.
The purpose of the invention and the technical problem to be solved are realized by adopting the following technical scheme.
The invention provides a preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, which comprises the following steps:
(1) dissolving 3-bromobenzaldehyde in a first solvent, then adding ammonia water and a catalyst, reacting in a hydrogen atmosphere, and filtering and concentrating after reaction to obtain a first reaction product;
(2) dissolving the first reaction product obtained in the step (1) in a second solvent, cooling to-20 ℃, slowly dropping inorganic acid, then adding an acetaldehyde aqueous solution, heating to a reflux temperature, reacting for 5-15 h, then concentrating under reduced pressure to 1/3 volume, adjusting the pH to 9-10, stirring overnight, carrying out suction filtration and recrystallization to obtain a second reaction product;
(3) dissolving the second reaction product obtained in the step (2) in a third solvent, dropwise adding a resolving agent, then preserving heat for 1-7H at 40-80 ℃, concentrating under reduced pressure to 1/2 volume, stirring overnight at room temperature, carrying out suction filtration and washing, adding the obtained solid into water, dissolving by slight heating, adjusting the pH value to 9-10, cooling to 10 ℃, stirring overnight, and carrying out suction filtration to obtain (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole.
The preparation method described above, wherein the first solvent in the step (1) is any one of methanol, ethanol, isopropanol, THF, acetonitrile, ethyl acetate or a combination of at least two thereof.
In the preparation method, the molar ratio of the ammonia water to the 3-bromobenzaldehyde in the step (1) is 1 (1-5).
In the preparation method, the catalyst in the step (1) includes palladium, nickel, platinum, rhodium or a compound thereof.
The preparation method described above, wherein the reaction conditions in the step (1) are: pressure: 1-4 atm, temperature: 10-50 ℃, time: 2-8 h.
In the preparation method, in the step (2), the inorganic acid includes hydrochloric acid, hydrobromic acid, hydrogen chloride gas or hydrogen bromide gas.
The preparation method described above, wherein the second solvent in step (2) is any one of water, methanol, ethanol acetonitrile, acetone, ethyl acetate, toluene, and benzene, or a combination of at least two of them.
In the preparation method, the molar ratio of the first reaction product to the acetaldehyde in the step (2) is 1 (1-5).
In the preparation method, in the step (3), the third solvent is any one of water, methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate and toluene, or a combination of at least two of the above.
In the preparation method, the resolving agent in the step (3) includes L (+) -tartaric acid, (+) -mandelic acid, (+) -camphor-10-sulfonic acid, L- (+) -glycine, (+) -2, 3-di-p-toluoyloxy succinic acid, (+) -1-phenylethanesulfonic acid and isomers or derivatives thereof.
By the technical scheme, the invention (name) at least has the following advantages:
(1) the invention uses 3-bromobenzaldehyde to prepare (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole through three-step reaction, firstly, the raw material 3-bromobenzaldehyde is a substance with low price and sufficient supply; secondly, the preparation method of the invention has simple steps, and the yield of each step is higher, and the waste of raw materials and reagents is less; finally, the invention produces few pollutants and is an environment-friendly process.
(2) The (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole obtained by the method has the advantages of high purity and high yield, and is suitable for industrial production.
(4) The method provided by the invention overcomes the problems that the conventional synthesis method is harsh in reaction conditions, unavailable in raw materials and expensive in price, is simple in step, mild in reaction conditions and high in yield, and saves the operation cost and the raw material cost.
In conclusion, the special preparation method of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole effectively solves the problems of difficult acquisition of raw materials, high price, low yield and the like in the existing synthesis method. The method has the advantages and practical values, does not have similar design publication or use but is really innovative in the same method, has larger improvement on the method or the function, has larger technical progress and produces good and practical effects, and has multiple enhanced effects compared with the existing preparation method of the (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, thereby being more practical, having wide industrial utilization value and being a novel, improved and practical new design.
The foregoing is a summary of the present invention, and in order to provide a clear understanding of the technical means of the present invention and to be implemented in accordance with the present specification, the following is a detailed description of the preferred embodiments of the present invention.
The specific process steps of the present invention are detailed in the following examples.
Detailed Description
The present invention is further illustrated below with reference to examples, which are intended to illustrate the invention and not to limit the scope of the invention. Furthermore, it should be understood that various changes and modifications of the present invention may be made by those skilled in the art after reading the teachings herein, and such equivalents may fall within the scope of the invention as defined in the appended claims.
It is to be noted that the experimental methods used in the following examples are all conventional methods unless otherwise specified. The materials and reagents used in the examples are commercially available unless otherwise specified.
The preparation process as described herein is carried out according to the following reaction equation:
wherein,
1: dissolving 3-bromobenzaldehyde in a first solvent, then adding ammonia water and a catalyst, reacting in a hydrogen atmosphere, and filtering and concentrating after reaction to obtain a first reaction product;
2: dissolving the first reaction product obtained in the step (1) in a second solvent, cooling to-20 ℃, slowly dropping inorganic acid, then adding an acetaldehyde aqueous solution, heating to a reflux temperature, reacting for 5-15 h, then concentrating under reduced pressure to 1/3 volume, adjusting the pH to 9-10, stirring overnight, carrying out suction filtration and recrystallization to obtain a second reaction product;
3: dissolving the second reaction product obtained in the step (2) in a third solvent, dropwise adding a resolving agent, then preserving heat for 1-7H at 40-80 ℃, concentrating under reduced pressure to 1/2 volume, stirring overnight at room temperature, carrying out suction filtration and washing, adding the obtained solid into water, dissolving by slight heating, adjusting the pH value to 9-10, cooling to 10 ℃, stirring overnight, and carrying out suction filtration to obtain (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole.
The details are described in the examples below.
Example 1
A500 ml hydrogenation vessel was charged with 200ml of methanol, 49.5g (0.268mol) of 3-bromobenzaldehyde, 5.0g of Raney's nickel catalyst (aqueous), and further with 27.34g of aqueous ammonia (25%, 0.402mol), to conduct a hydrogen substitution reaction: the temperature is 30 ℃, the hydrogen pressure is 2atm, and the reaction time is 4 h. After the reaction, the solution was filtered and concentrated to obtain 48.6g of m-bromobenzylamine as the first reaction product, with a yield of 98.2% and a gas phase purity of 94.9%.
60ml of water and 31.0g (0.167mol) of the first reaction product, m-bromobenzylamine, were added to a 250ml four-necked flask, the temperature was lowered to 0 ℃ and 30ml of hydrochloric acid was slowly dropped, 22.04g of an aqueous acetaldehyde solution (40%, 0.200mol) was added thereto, and the mixture was heated to reflux reaction for 9 hours. Then the solution is decompressed and concentrated to about 1/3 volume, the pH value is adjusted to 9-10 by 10 percent sodium hydroxide, the solution is stirred overnight, and the solution is filtered by suction and recrystallized by toluene, so that 27.73g of a second reaction product is obtained, the yield is 78.3 percent, and the HPLC purity is 96.2 percent.
21.21g (0.10mol) of the second reaction product was dissolved in 120ml of absolute ethanol, 150ml of ethanol solution of 18.01g L (+) -tartaric acid (0.12mol) was slowly added dropwise, and after completion of the addition, the mixture was incubated at 60 ℃ for 3 hours. The solution was concentrated under reduced pressure to 1/2 volumes, stirred overnight at room temperature, filtered with suction and washed with a small amount of ethanol, and dried. The resulting solid was added to 220ml of water, dissolved at 30 ℃, slowly dropped with 10% sodium hydroxide to adjust the pH to 9-10, cooled to 10 ℃ and stirred overnight. The solution is filtered, washed and dried to obtain 8.59g of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the yield is 81.0 percent, and the HPLC purity is 99.59 percent.
Example 2
A500 ml hydrogenation vessel was charged with 200ml of methanol, 49.5g (0.268mol) of 3-bromobenzaldehyde, 5.0g of Raney's nickel catalyst (aqueous), and further with 27.34g of aqueous ammonia (25%, 0.402mol), to conduct a hydrogen substitution reaction: the temperature is 30 ℃, the hydrogen pressure is 2atm, and the reaction time is 4 h. After the reaction, the solution was filtered and concentrated to obtain 48.6g of m-bromobenzylamine as the first reaction product, with a yield of 98.2% and a gas phase purity of 94.9%.
In a 250ml four-necked flask, 60ml of water and 31.0g (0.167mol) of m-bromobenzylamine as the first reaction product were charged, the temperature was lowered to 0 ℃ and 50ml of hydrobromic acid was slowly dropped, and 22.04g of an aqueous acetaldehyde solution (40%, 0.200mol) was further added thereto, and the temperature was raised to reflux reaction for 9 hours. Then the solution is decompressed and concentrated to about 1/3 volume, the pH value is adjusted to 9-10 by 10 percent sodium hydroxide, the solution is stirred overnight, and the solution is filtered by suction and recrystallized by toluene, so that 29.44g of a second reaction product is obtained, the yield is 83.1 percent, and the HPLC purity is 97.6 percent.
21.21g (0.10mol) of the second reaction product was dissolved in 120ml of absolute ethanol, and a 150ml ethanol solution of 18.01g L (+) -tartaric acid (0.12mol) was slowly added dropwise, followed by incubation at 60 ℃ for 3 hours after completion of the addition. The solution was concentrated under reduced pressure to 1/2 volumes, stirred overnight at room temperature, filtered with suction and washed with a small amount of ethanol, and dried. The resulting solid was added to 220ml of water, dissolved at 30 ℃, slowly dropped with 10% sodium hydroxide to adjust the pH to 9-10, cooled to 10 ℃ and stirred overnight. The solution is filtered, washed and dried to obtain 8.59g of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the yield is 81.0 percent, and the HPLC purity is 99.59 percent.
Example 3
A500 ml hydrogenation vessel was charged with 200ml of methanol, 49.5g (0.268mol) of 3-bromobenzaldehyde, 5.0g of Raney's nickel catalyst (aqueous), and further with 27.34g of aqueous ammonia (25%, 0.402mol), to conduct a hydrogen substitution reaction: the temperature is 30 ℃, the hydrogen pressure is 2atm, and the reaction time is 4 h. After the reaction, the solution was filtered and concentrated to obtain 48.6g of m-bromobenzylamine as the first reaction product, with a yield of 98.2% and a gas phase purity of 94.9%.
In a 250ml four-necked flask, 60ml of water and 31.0g (0.167mol) of m-bromobenzylamine as the first reaction product were charged, the temperature was lowered to 0 ℃ and 50ml of hydrobromic acid was slowly dropped, and 22.04g of an aqueous acetaldehyde solution (40%, 0.200mol) was further added thereto, and the temperature was raised to reflux reaction for 9 hours. Then the solution is decompressed and concentrated to about 1/3 volume, the pH value is adjusted to 9-10 by 10 percent sodium hydroxide, the solution is stirred overnight, and the solution is filtered by suction and recrystallized by toluene, so that 29.44g of a second reaction product is obtained, the yield is 83.1 percent, and the HPLC purity is 97.6 percent.
21.21g (0.10mol) of the second reaction product was dissolved in 120ml of anhydrous ethanol, and a 150ml ethanol solution of 28.12g of 1R- (-) -camphorsulfonic acid (0.12mol) was slowly dropped, followed by incubation at 60 ℃ for 3 hours after completion of the dropping. The solution was concentrated under reduced pressure to 1/2 volumes, stirred overnight at room temperature, filtered with suction and washed with a small amount of ethanol, and dried. The resulting solid was added to 220ml of water, dissolved at 30 ℃, slowly dropped with 10% sodium hydroxide to adjust the pH to 9-10, cooled to 10 ℃ and stirred overnight. The solution is filtered, washed and dried to obtain 9.12g of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the yield is 86.0 percent, and the HPLC purity is 99.64 percent.
Example 4
A500 ml hydrogenation vessel was charged with 200ml of methanol, 49.5g (0.268mol) of 3-bromobenzaldehyde, 5.0g of Raney's nickel catalyst (aqueous), and further with 27.34g of aqueous ammonia (25%, 0.402mol), to conduct a hydrogen substitution reaction: the temperature is 30 ℃, the hydrogen pressure is 2atm, and the reaction time is 4 h. After the reaction, the solution was filtered and concentrated to obtain 48.6g of m-bromobenzylamine as the first reaction product, with a yield of 98.2% and a gas phase purity of 94.9%.
60ml of water and 31.0g (0.167mol) of the first reaction product, m-bromobenzylamine, were added to a 250ml four-necked flask, the temperature was lowered to 0 ℃ and 30ml of hydrochloric acid was slowly dropped, 22.04g of an aqueous acetaldehyde solution (40%, 0.200mol) was added thereto, and the mixture was heated to reflux reaction for 9 hours. Then the solution is decompressed and concentrated to about 1/3 volume, the pH value is adjusted to 9-10 by 10 percent sodium hydroxide, the solution is stirred overnight, and the solution is filtered by suction and recrystallized by toluene, so that 27.73g of a second reaction product is obtained, the yield is 78.3 percent, and the HPLC purity is 96.2 percent.
21.21g (0.10mol) of the second reaction product was dissolved in 120ml of anhydrous ethanol, and a 150ml ethanol solution of 28.12g of 1R- (-) -camphorsulfonic acid (0.12mol) was slowly dropped, followed by incubation at 60 ℃ for 3 hours after completion of the dropping. The solution was concentrated under reduced pressure to 1/2 volumes, stirred overnight at room temperature, filtered with suction and washed with a small amount of ethanol, and dried. The resulting solid was added to 220ml of water, dissolved at 30 ℃, slowly dropped with 10% sodium hydroxide to adjust the pH to 9-10, cooled to 10 ℃ and stirred overnight. The solution is filtered, washed and dried to obtain 9.12g of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the yield is 86.0 percent, and the HPLC purity is 99.64 percent.
Example 5
A500 ml hydrogenation vessel was charged with 200ml of methanol, 49.5g (0.268mol) of 3-bromobenzaldehyde, 1.0g of palladium on carbon catalyst (5%, water content 55%), and further 27.34g of aqueous ammonia (25%, 0.402mol) to conduct a hydrogen substitution reaction: the temperature is 30 ℃, the hydrogen pressure is 2atm, and the reaction time is 4 h. After the reaction, the solution was filtered and concentrated to obtain 48.1g of the first reaction product, m-bromobenzylamine, with a yield of 97.2% and a gas phase purity of 85.1%.
In a 250ml four-necked flask, 60ml of water and 31.0g (0.167mol) of m-bromobenzylamine as the first reaction product were charged, the temperature was lowered to 0 ℃ and 50ml of hydrobromic acid was slowly dropped, and 22.04g of an aqueous acetaldehyde solution (40%, 0.200mol) was further added thereto, and the temperature was raised to reflux reaction for 9 hours. Then the solution is decompressed and concentrated to about 1/3 volume, the pH value is adjusted to 9-10 by 10 percent sodium hydroxide, the solution is stirred overnight, and the solution is filtered by suction and recrystallized by toluene, so that 29.44g of a second reaction product is obtained, the yield is 83.1 percent, and the HPLC purity is 97.6 percent.
21.21g (0.10mol) of the second reaction product was dissolved in 120ml of anhydrous ethanol, and a 150ml ethanol solution of 28.12g of 1R- (-) -camphorsulfonic acid (0.12mol) was slowly dropped, followed by incubation at 60 ℃ for 3 hours after completion of the dropping. The solution was concentrated under reduced pressure to 1/2 volumes, stirred overnight at room temperature, filtered with suction and washed with a small amount of ethanol, and dried. The resulting solid was added to 220ml of water, dissolved at 30 ℃, slowly dropped with 10% sodium hydroxide to adjust the pH to 9-10, cooled to 10 ℃ and stirred overnight. The solution is filtered, washed and dried to obtain 9.12g of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the yield is 86.0 percent, and the HPLC purity is 99.64 percent.
Example 6
A500 ml hydrogenation vessel was charged with 200ml of methanol, 49.5g (0.268mol) of 3-bromobenzaldehyde, 1.0g of palladium on carbon catalyst (5%, water content 55%), and further 27.34g of aqueous ammonia (25%, 0.402mol) to conduct a hydrogen substitution reaction: the temperature is 30 ℃, the hydrogen pressure is 2atm, and the reaction time is 4 h. After the reaction, the solution was filtered and concentrated to obtain 48.1g of the first reaction product, m-bromobenzylamine, with a yield of 97.2% and a gas phase purity of 85.1%.
In a 250ml four-necked flask, 60ml of water and 31.0g (0.167mol) of m-bromobenzylamine as the first reaction product were charged, the temperature was lowered to 0 ℃ and 50ml of hydrobromic acid was slowly dropped, and 22.04g of an aqueous acetaldehyde solution (40%, 0.200mol) was further added thereto, and the temperature was raised to reflux reaction for 9 hours. Then the solution is decompressed and concentrated to about 1/3 volume, the pH value is adjusted to 9-10 by 10 percent sodium hydroxide, the solution is stirred overnight, and the solution is filtered by suction and recrystallized by toluene, so that 29.44g of a second reaction product is obtained, the yield is 83.1 percent, and the HPLC purity is 97.6 percent.
21.21g (0.10mol) of the second reaction product was dissolved in 120ml of absolute ethanol, and a 150ml ethanol solution of 18.01g L (+) -tartaric acid (0.12mol) was slowly added dropwise, followed by incubation at 60 ℃ for 3 hours after completion of the addition. The solution was concentrated under reduced pressure to 1/2 volumes, stirred overnight at room temperature, filtered with suction and washed with a small amount of ethanol, and dried. The resulting solid was added to 220ml of water, dissolved at 30 ℃, slowly dropped with 10% sodium hydroxide to adjust the pH to 9-10, cooled to 10 ℃ and stirred overnight. The solution is filtered, washed and dried to obtain 8.59g of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the yield is 81.0 percent, and the HPLC purity is 99.59 percent.
Example 7
A500 ml hydrogenation vessel was charged with 200ml of methanol, 49.5g (0.268mol) of 3-bromobenzaldehyde, 1.0g of palladium on carbon catalyst (5%, water content 55%), and further 27.34g of aqueous ammonia (25%, 0.402mol) to conduct a hydrogen substitution reaction: the temperature is 30 ℃, the hydrogen pressure is 2atm, and the reaction time is 4 h. After the reaction, the solution was filtered and concentrated to obtain 48.1g of the first reaction product, m-bromobenzylamine, with a yield of 97.2% and a gas phase purity of 85.1%.
60ml of water and 31.0g (0.167mol) of the first reaction product, m-bromobenzylamine, were added to a 250ml four-necked flask, the temperature was lowered to 0 ℃ and 30ml of hydrochloric acid was slowly dropped, 22.04g of an aqueous acetaldehyde solution (40%, 0.200mol) was added thereto, and the mixture was heated to reflux reaction for 9 hours. Then the solution is decompressed and concentrated to about 1/3 volume, the pH value is adjusted to 9-10 by 10 percent sodium hydroxide, the solution is stirred overnight, and the solution is filtered by suction and recrystallized by toluene, so that 27.73g of a second reaction product is obtained, the yield is 78.3 percent, and the HPLC purity is 96.2 percent.
21.21g (0.10mol) of the second reaction product was dissolved in 120ml of anhydrous ethanol, and a 150ml ethanol solution of 28.12g of 1R- (-) -camphorsulfonic acid (0.12mol) was slowly dropped, followed by incubation at 60 ℃ for 3 hours after completion of the dropping. The solution was concentrated under reduced pressure to 1/2 volumes, stirred overnight at room temperature, filtered with suction and washed with a small amount of ethanol, and dried. The resulting solid was added to 220ml of water, dissolved at 30 ℃, slowly dropped with 10% sodium hydroxide to adjust the pH to 9-10, cooled to 10 ℃ and stirred overnight. The solution is filtered, washed and dried to obtain 9.12g of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the yield is 86.0 percent, and the HPLC purity is 99.64 percent.
Example 8
A500 ml hydrogenation vessel was charged with 200ml of methanol, 49.5g (0.268mol) of 3-bromobenzaldehyde, 1.0g of palladium on carbon catalyst (5%, water content 55%), and further 27.34g of aqueous ammonia (25%, 0.402mol) to conduct a hydrogen substitution reaction: the temperature is 30 ℃, the hydrogen pressure is 2atm, and the reaction time is 4 h. After the reaction, the solution was filtered and concentrated to obtain 48.1g of the first reaction product, m-bromobenzylamine, with a yield of 97.2% and a gas phase purity of 85.1%.
60ml of water and 31.0g (0.167mol) of the first reaction product, m-bromobenzylamine, were added to a 250ml four-necked flask, the temperature was lowered to 0 ℃ and 30ml of hydrochloric acid was slowly dropped, 22.04g of an aqueous acetaldehyde solution (40%, 0.200mol) was added thereto, and the mixture was heated to reflux reaction for 9 hours. Then the solution is decompressed and concentrated to about 1/3 volume, the pH value is adjusted to 9-10 by 10 percent sodium hydroxide, the solution is stirred overnight, and the solution is filtered by suction and recrystallized by toluene, so that 27.73g of a second reaction product is obtained, the yield is 78.3 percent, and the HPLC purity is 96.2 percent.
21.21g (0.10mol) of the second reaction product was dissolved in 120ml of absolute ethanol, and a 150ml ethanol solution of 18.01g L (+) -tartaric acid (0.12mol) was slowly added dropwise, followed by incubation at 60 ℃ for 3 hours after completion of the addition. The solution was concentrated under reduced pressure to 1/2 volumes, stirred overnight at room temperature, filtered with suction and washed with a small amount of ethanol, and dried. The resulting solid was added to 220ml of water, dissolved at 30 ℃, slowly dropped with 10% sodium hydroxide to adjust the pH to 9-10, cooled to 10 ℃ and stirred overnight. The solution is filtered, washed and dried to obtain 8.59g of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, the yield is 81.0 percent, and the HPLC purity is 99.59 percent.
In conclusion, the (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole can be prepared by using 3-bromobenzaldehyde through three steps of reactions, and firstly, the raw material 3-bromobenzaldehyde is a cheap substance and is sufficiently supplied; secondly, the preparation method of the invention has simple steps, and the yield of each step is higher, and the waste of raw materials and reagents is less; finally, the invention produces few pollutants and is an environment-friendly process. The (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole obtained by the method has the advantages of high purity and high yield, and is suitable for industrial production. The method provided by the invention overcomes the problems that the conventional synthesis method is harsh in reaction conditions, unavailable in raw materials and expensive in price, is simple in step, mild in reaction conditions and high in yield, and saves the operation cost and the raw material cost.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. A process for the preparation of (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole, wherein the process comprises the steps of:
(1) dissolving 3-bromobenzaldehyde in a first solvent, then adding ammonia water and a catalyst, reacting in a hydrogen atmosphere, and filtering and concentrating after reaction to obtain a first reaction product;
(2) dissolving the first reaction product obtained in the step (1) in a second solvent, cooling to-20 ℃, slowly dropping inorganic acid, then adding an acetaldehyde aqueous solution, heating to a reflux temperature, reacting for 5-15 h, then concentrating under reduced pressure to 1/3 volume, adjusting the pH to 9-10, stirring overnight, carrying out suction filtration and recrystallization to obtain a second reaction product;
(3) dissolving the second reaction product obtained in the step (2) in a third solvent, dropwise adding a resolving agent, then preserving heat for 1-7H at 40-80 ℃, concentrating under reduced pressure to 1/2 volume, stirring overnight at room temperature, carrying out suction filtration and washing, adding the obtained solid into water, dissolving by slight heating, adjusting the pH value to 9-10, cooling to 10 ℃, stirring overnight, and carrying out suction filtration to obtain (1R) -5-bromo-2, 3-dihydro-1-methyl-1H-isoindole.
2. The method according to claim 1, wherein the first solvent in step (1) is any one of methanol, ethanol, isopropanol, THF, acetonitrile, ethyl acetate, or a combination of at least two thereof.
3. The preparation method according to claim 1, wherein the molar ratio of the ammonia water to the 3-bromobenzaldehyde in the step (1) is 1 (1-5).
4. The production method according to claim 1, wherein the catalyst in the step (1) comprises palladium, nickel, platinum, rhodium or a compound thereof.
5. The production method according to claim 1, wherein the reaction conditions in the step (1) are: pressure: 1-4 atm, temperature: 10-50 ℃, time: 2-8 h.
6. The production method according to claim 1, wherein the inorganic acid in the step (2) comprises hydrochloric acid, hydrobromic acid, hydrogen chloride gas or hydrogen bromide gas.
7. The preparation method according to claim 1, wherein the second solvent in the step (2) is any one of water, methanol, ethanol acetonitrile, acetone, ethyl acetate, toluene and benzene or a combination of at least two of the above.
8. The preparation method according to claim 1, wherein the molar ratio of the first reaction product to the acetaldehyde in the step (2) is 1 (1-5).
9. The preparation method according to claim 1, wherein the third solvent in the step (3) is any one of water, methanol, ethanol, isopropanol, acetonitrile, acetone, ethyl acetate and toluene or a combination of at least two of the above.
10. The preparation method of claim 1, wherein the resolving agent in the step (3) comprises L (+) -tartaric acid, (+) -mandelic acid, (+) -camphor-10-sulfonic acid, L- (+) -glycine, (+) -2, 3-di-p-toluoyloxy succinic acid, (+) -1-phenylethanesulfonic acid and isomers thereof or derivatives thereof.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111718290A (en) * | 2020-07-22 | 2020-09-29 | 苏州爱玛特生物科技有限公司 | Synthesis method of multi-configuration isoindoline-1-carboxylic acid amino acid compound |
| CN113429333A (en) * | 2021-07-08 | 2021-09-24 | 江苏法安德医药科技有限公司 | Synthesis method of gatifloxacin intermediate |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020173517A1 (en) * | 1999-10-19 | 2002-11-21 | Sato Pharmaceutical Co., Ltd. | 4-Oxoquinolizine antimicrobial having 2-pyridone skeleton as partial structure |
| CN1704397A (en) * | 2004-05-25 | 2005-12-07 | 张炳庚 | Method for preparing p-fluorobenzylamine by using nano nickel as catalyst |
| CN105189508A (en) * | 2013-03-19 | 2015-12-23 | 默沙东公司 | Cycloalkyl nitrile pyrazolo pyridones as JANUS kinase inhibitors |
| CN106552661A (en) * | 2016-10-28 | 2017-04-05 | 中南民族大学 | A kind of nitrogen-doped carbon material load cobalt catalyst and the method for preparing aminated compoundss using its catalytic hydrogenating reduction amination |
| CN106957255A (en) * | 2017-03-28 | 2017-07-18 | 上海馨远医药科技有限公司 | Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application |
-
2019
- 2019-12-09 CN CN201911250935.4A patent/CN110938028B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20020173517A1 (en) * | 1999-10-19 | 2002-11-21 | Sato Pharmaceutical Co., Ltd. | 4-Oxoquinolizine antimicrobial having 2-pyridone skeleton as partial structure |
| CN1704397A (en) * | 2004-05-25 | 2005-12-07 | 张炳庚 | Method for preparing p-fluorobenzylamine by using nano nickel as catalyst |
| CN105189508A (en) * | 2013-03-19 | 2015-12-23 | 默沙东公司 | Cycloalkyl nitrile pyrazolo pyridones as JANUS kinase inhibitors |
| CN106552661A (en) * | 2016-10-28 | 2017-04-05 | 中南民族大学 | A kind of nitrogen-doped carbon material load cobalt catalyst and the method for preparing aminated compoundss using its catalytic hydrogenating reduction amination |
| CN106957255A (en) * | 2017-03-28 | 2017-07-18 | 上海馨远医药科技有限公司 | Methylisoindoline of 5 bromines of one kind (R) N Boc 1 and its preparation method and application |
Non-Patent Citations (4)
| Title |
|---|
| FEI LING ET AL.: ""Traceless Directing Group Assisted Cobalt‐Catalyzed C−H Carbonylation of Benzylamines"", 《ADVANCED SYNTHESIS & CATALYSIS》 * |
| KITABATAKE, M ET AL.: ""FACILE SYNTHESIS OF 1-ARYL-2,3-DIHYDRO-1H-ISOINDOLES BY CYCLIZATION OF N-FORMYLIMINIUM ION VIA GEOMETRICALLY DISFAVORED 5-ENDO-TRIG PROCESS"", 《HETEROCYCLES》 * |
| 吴孝国等: ""加雷沙星的合成"", 《中国现代应用药学》 * |
| 邢存章主编: "《有机化学 下》", 31 October 2001, 山东大学出版社 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111718290A (en) * | 2020-07-22 | 2020-09-29 | 苏州爱玛特生物科技有限公司 | Synthesis method of multi-configuration isoindoline-1-carboxylic acid amino acid compound |
| CN111718290B (en) * | 2020-07-22 | 2022-11-25 | 苏州爱玛特生物科技有限公司 | Synthesis method of multi-configuration isoindoline-1-carboxylic acid amino acid compound |
| CN113429333A (en) * | 2021-07-08 | 2021-09-24 | 江苏法安德医药科技有限公司 | Synthesis method of gatifloxacin intermediate |
| CN113429333B (en) * | 2021-07-08 | 2022-03-04 | 江苏法安德医药科技有限公司 | Synthesis method of gatifloxacin intermediate |
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