CN104945265A - Synthetic method for indan-2-amine - Google Patents
Synthetic method for indan-2-amine Download PDFInfo
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- CN104945265A CN104945265A CN201510313587.6A CN201510313587A CN104945265A CN 104945265 A CN104945265 A CN 104945265A CN 201510313587 A CN201510313587 A CN 201510313587A CN 104945265 A CN104945265 A CN 104945265A
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- 0 *C(Cc1c2cccc1)C2=O Chemical compound *C(Cc1c2cccc1)C2=O 0.000 description 2
- LMHHFZAXSANGGM-UHFFFAOYSA-N NC1Cc2ccccc2C1 Chemical compound NC1Cc2ccccc2C1 LMHHFZAXSANGGM-UHFFFAOYSA-N 0.000 description 1
- QNXSIUBBGPHDDE-UHFFFAOYSA-N O=C1c2ccccc2CC1 Chemical compound O=C1c2ccccc2CC1 QNXSIUBBGPHDDE-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention relates to a synthetic method for indan-2-amine. According to the synthetic method, the target product indan-2-amine is obtained by the following steps: adopting 2-indanone as a raw material, performing substitution reaction on 2-indanone and a halogenated agent to obtain a compound I, performing reduction reaction on the compound I to obtain a compound II, and finally performing amination reaction. Compared with the prior art, the synthetic method provided by the invention has the advantages that the related reactions are simple, the after-treatment is convenient, the raw material is cheap and easy to obtain, the yield is relatively high, and the reaction conditions are mild, thereby being relatively ideal for indan-2-amine preparation.
Description
Technical field
The invention belongs to pharmaceutical chemistry synthesis technical field, be specifically related to the synthetic method of the amino indenes of 2-.
Background technology
The amino indenes of 2-is important medicine, Chemical Manufacture intermediate, the intermediate that can synthesize as antihypertensive drug delapril and the synthesis material of bronchodilator QAB-149.Delapril, it is light to severe primary, kidney and renovascular hypertension that this medicine is mainly used in treatment.QAB-149, long-acting suction β
2receptor stimulant, is applicable to the maintaining treatment of Adult chronic's obstructive pulmonary disease patient.
The amino indenes primary synthetic methods of 2-of current report has four kinds:
Wang Jin Jing etc. are at document Sci.Tech.Eengrg, 11,8001 synthetic methods reporting the amino indenes of a kind of 2-: take indenes as raw material, generate 2-indone with formic acid/hydrogen peroxide generation addition reaction, again indone and oxammonium hydrochloride are obtained by reacting 2-indenes oxime, then carry out reduction reaction and obtain the amino indenes of 2-.This route yield is lower, is not desirable industrializing synthesis route.
Goeksu is at document Tetrahedron, and 61,2801. reports are with the synthetic method of the amino indenes of a kind of 2-: with 2-indanol for raw material, with hydrazoic acid, Mitsunobu occurs and react, reaction product restores, and obtains target product.This kind of preparation method is not suitable for suitability for industrialized production, and hydrazoic acid is a kind of explosive material, is subject to clashing into just blast, is unfavorable for reaction controlling.
JP04124161 discloses the synthetic method of the amino indenes of a kind of 2-: with 1-indone for raw material, introduces oxime at carbonyl ortho position, then reaction product reduction is obtained target product.At the adjacent reagent for introducing used by oxime of carbonyl, as nitrous acid straight butyl, price is high, is unfavorable for preserving, extremely unstable.This kind of method is also not suitable for suitability for industrialized production.
Roche reports the synthetic method of the amino indenes of a kind of 2-at document Org.Proces Res.Dev 2001,5,16., take triketohydrindene hydrate as raw material, under the action of an acid, forms oxime with azanol condensation, then reaction product reduction is obtained target product.This route is short, can " one kettle way " react, but expensive starting materials, and reaction yield is not high, by product is more.The cost of this kind of method target product separation and purification is higher, is applied to suitability for industrialized production and still has very large difficulty.
Summary of the invention
The object of the present invention is to provide the amino indenes synthetic method of a kind of 2-of novelty, present method has that cheaper starting materials is easy to get, easy and simple to handle, Atom economy is high, be easy to the advantages such as suitability for industrialized production.
The object of the invention is achieved through the following technical solutions:
A synthetic method for the amino indenes of 2-, is characterized in that, comprise the steps:
(1) at 50 ~ 80 DEG C, use halogenating agent and the catalyzer of 1-indone, 0.5 ~ 3 equivalent 1-indone, in the mixed solvent of chloroform or chloroform and ethyl acetate, react 0.5 ~ 24h, obtain Compound I, the structural formula of Compound I is:
wherein X is any one in Cl, Br, I;
(2) at 15 DEG C ~ 45 DEG C, with the alcoholic solvent of C1 ~ C4 such as alcoholic solvent or methyl alcohol of the C1 ~ C4 such as methyl alcohol and the mixed solvent of ether solvent, Compound I is dissolved, add be equivalent to 3 ~ 60 equivalent chemical combination I go back original reagent, reaction 1 ~ 26h, is separated and obtains Compound II per; Compound II per structural formula is:
wherein X is any one in Cl, Br, I;
(3) at 25 DEG C at 90 DEG C, dissolved by Compound II per with organic solvent, add the amination reagent of 1 ~ 5 equivalents of compound II, add catalyzer, reaction 3 ~ 24h, obtain the shape of the amino indenes of 2-or its salt, the amino indenes structural formula of 2-is:
Halogenating agent described in step (1) is chlorine, N-chlorosuccinimide, cupric bromide, pyridinium tribromide drone salt, N-bromo-succinimide, hypohalite, sulfonyl halide, halogenation sulfoxide or iodine;
Catalyzer described in step (1) can be Lewis acid, mineral alkali or organic bases;
Lewis acid can be AlC1
3, ZnCl
2or BF
3;
Ether solvent described in step (2) can be tetrahydrofuran (THF), ether, methyl tertiary butyl ether;
Amination reagent described in step (3) can be NH
3, potassium phthalimide or sodium amide;
Organic solvent described in step (3) is following one or arbitrary combination between them: alcohol, acetonitrile, methyl-sulphoxide, acetone, butanone, the tetrahydrofuran (THF) of the C1-C4 such as methane amide, DMF, water, methyl alcohol, ethanol, propyl carbinol;
The catalyzer adopted described in step (3) is the ammonium salt class such as salt compounded of iodine and ammonium chloride, ammonium nitrate, ammonium acetate.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.In addition should be understood that those skilled in the art can make various change or amendment to the present invention, and these equivalent form of values fall within the application's appended claims limited range equally after the content of having read the present invention's instruction.
Step (1):
Embodiment 1
The preparation of Compound I:
In the dry three-necked bottle of 250ml, add 1-indone 16.0g, cupric bromide 59.5g, chloroform 50ml, ethyl acetate 50ml, heated and stirred back flow reaction 1h.Reaction is cooled to room temperature, and filtering solid, removes solvent under reduced pressure, obtains crude product.By crude product ethyl alcohol recrystallization, obtain white solid bromo compound I 24.52g.Yield 96%.
Step (2):
Embodiment 2
The preparation of Compound II per:
In the dry three-necked bottle of 250ml, add bromo compound I 22.0g, 5% palladium carbon 0.67g, adds ethanol 250ml, pass into hydrogen, reaction pressure controls at 2.5MPa, and the mol ratio of bromo compound I and hydrogen is 1: 50, stirring at room temperature reaction 24h, suction filtration Recover palladium carbon, steaming desolventizes.Obtain oily bromo compound II 18.5g.Yield 90%.
Step (3):
Embodiment 3
The preparation of the amino indenes of target product 2-:
In the dry three-necked bottle of band 500ml, add potassium phthalimide 21.0g, bromo compound II 18.5g, dry DMF 250ml.Be warming up to 80 DEG C of stirring reaction 6h, naturally cool to room temperature, remove solvent afforded crude material under reduced pressure.Crude product is dissolved in 200ml ethanol, drips 80% hydrazine hydrate 7.05g (using 50ml dissolve with ethanol), dropwise, back flow reaction 2h, filtering solid at 50 DEG C, with washing with alcohol solid twice, decompression removing filtrate obtains crude product.Crude product being dissolved in 100ml massfraction is 20% dilute hydrochloric acid, stirs 0.5h, with 80ml washed with diethylether water layer twice, then regulates water layer pH to 12 ~ 13 with 20% sodium hydroxide solution, filters to obtain target product white solid 11.3g.Yield 90.4%.
Claims (8)
1. a synthetic method for the amino indenes of 2-, is characterized in that, comprise the steps:
(1) at 50 ~ 80 DEG C, use halogenating agent and the catalyzer of 1-indone, 0.5 ~ 3 equivalent 1-indone, in the mixed solvent of chloroform or chloroform and ethyl acetate, react 0.5 ~ 24h, obtain Compound I, the structural formula of Compound I is:
wherein X is any one in Cl, Br, I;
(2) at 15 DEG C ~ 45 DEG C, with the alcoholic solvent of C1 ~ C4 such as alcoholic solvent or methyl alcohol of the C1 ~ C4 such as methyl alcohol and the mixed solvent of ether solvent, Compound I is dissolved, add be equivalent to 3 ~ 60 equivalents of compound I go back original reagent, reaction 1 ~ 26h, separation obtains Compound II per, and Compound II per structural formula is:
wherein X is any one in Cl, Br, I;
(3) at 25 DEG C at 90 DEG C, with organic solvent, Compound II per is dissolved, adds the amination reagent of 1 ~ 5 equivalents of compound II, add catalyzer, reaction 3 ~ 24h, obtain the form of the amino indenes of 2-or its salt;
The amino indenes structural formula of 2-is:
2. the amino indenes synthetic method of a kind of 2-as claimed in claim 1, is characterized in that: the halogenating agent described in step (1) is chlorine, N-chlorosuccinimide, cupric bromide, pyridinium tribromide drone salt, N-bromo-succinimide, hypohalite, sulfonyl halide, halogenation sulfoxide or iodine.
3. the amino indenes synthetic method of a kind of 2-as claimed in claim 1, is characterized in that: the catalyzer described in step (1) can be Lewis acid, mineral alkali or organic bases.
4. the amino indenes synthetic method of a kind of 2-as claimed in claim 3, is characterized in that: Lewis acid can be AlCl
3, ZnCl
2or BF
3.
5. the amino indenes synthetic method of a kind of 2-as claimed in claim 1, is characterized in that: ether solvent described in step (2) can be tetrahydrofuran (THF), ether, methyl tertiary butyl ether.
6. the amino indenes synthetic method of a kind of 2-as claimed in claim 1, is characterized in that: amination reagent described in step (3) can be NH
3, potassium phthalimide or sodium amide.
7. the amino indenes synthetic method of a kind of 2-as claimed in claim 1, it is characterized in that: organic solvent described in step (3) is the following a kind of or C1-C4 such as arbitrary combination methane amide, DMF, water, methyl alcohol, ethanol, propyl carbinol between them alcohol, acetonitrile, methyl-sulphoxide, acetone, butanone, tetrahydrofuran (THF).
8. the amino indenes synthetic method of a kind of 2-as claimed in claim 1, is characterized in that: the catalyzer adopted described in step (3) is the ammonium salt class such as salt compounded of iodine and ammonium chloride, ammonium nitrate, ammonium acetate.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106221283A (en) * | 2016-07-22 | 2016-12-14 | 河南科技大学 | A kind of extracting method of black rice anthocyanin |
| CN109438253A (en) * | 2018-10-08 | 2019-03-08 | 江苏苏利精细化工股份有限公司 | A kind of method of novel synthesis 2- amino indenes |
| CN109956878A (en) * | 2017-12-26 | 2019-07-02 | 江苏道博化工有限公司 | The synthetic method of solvent dye intermediate |
| CN110229067A (en) * | 2019-06-05 | 2019-09-13 | 南京焕然生物科技有限公司 | A kind of 2- amino indenes preparation method |
| CN115160210A (en) * | 2022-08-01 | 2022-10-11 | 上海巽田科技股份有限公司 | Method for synthesizing heterobicyclic compound |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110256228A (en) * | 2019-07-10 | 2019-09-20 | 江苏颖盛化工有限公司 | The synthetic method of novel DL-naproxen |
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| US20100113512A1 (en) * | 2008-10-30 | 2010-05-06 | Diane Michele Ignar | Method of treatment using novel antagonists or inverse agonists at opioid receptors |
| CN104628575A (en) * | 2015-02-09 | 2015-05-20 | 许昌豪丰化学科技有限公司 | Preparation method of 2-aminoindan |
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2015
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100113512A1 (en) * | 2008-10-30 | 2010-05-06 | Diane Michele Ignar | Method of treatment using novel antagonists or inverse agonists at opioid receptors |
| CN104628575A (en) * | 2015-02-09 | 2015-05-20 | 许昌豪丰化学科技有限公司 | Preparation method of 2-aminoindan |
Non-Patent Citations (1)
| Title |
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| 汪金璟等: "2-氨基茚满的合成研究", 《科学技术与工程》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106221283A (en) * | 2016-07-22 | 2016-12-14 | 河南科技大学 | A kind of extracting method of black rice anthocyanin |
| CN109956878A (en) * | 2017-12-26 | 2019-07-02 | 江苏道博化工有限公司 | The synthetic method of solvent dye intermediate |
| CN109956878B (en) * | 2017-12-26 | 2021-12-17 | 江苏道博化工有限公司 | Synthetic method of solvent dye intermediate |
| CN109438253A (en) * | 2018-10-08 | 2019-03-08 | 江苏苏利精细化工股份有限公司 | A kind of method of novel synthesis 2- amino indenes |
| CN110229067A (en) * | 2019-06-05 | 2019-09-13 | 南京焕然生物科技有限公司 | A kind of 2- amino indenes preparation method |
| CN115160210A (en) * | 2022-08-01 | 2022-10-11 | 上海巽田科技股份有限公司 | Method for synthesizing heterobicyclic compound |
| CN115160210B (en) * | 2022-08-01 | 2023-10-24 | 上海巽田科技股份有限公司 | Method for synthesizing heterobicyclic compounds |
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