CN107056630B - Indane derivative, and synthesis method and medical application thereof - Google Patents

Indane derivative, and synthesis method and medical application thereof Download PDF

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CN107056630B
CN107056630B CN201710058304.7A CN201710058304A CN107056630B CN 107056630 B CN107056630 B CN 107056630B CN 201710058304 A CN201710058304 A CN 201710058304A CN 107056630 B CN107056630 B CN 107056630B
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indan
dihydro
nmr
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ethyl acetate
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廖晨钟
张兴星
肖炫
詹美苗
马靖雯
朱蜜蜜
李银凤
管丽
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Hefei Polytechnic University
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
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    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/16—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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Abstract

The invention discloses an indane derivative, a synthesis method and a medical application thereof, wherein the indane derivative has a structural general formula as follows:

Description

Indane derivative, and synthesis method and medical application thereof
Technical Field
The invention relates to the technical field of drug synthesis, in particular to novel indane derivatives, a synthesis method thereof and a pharmaceutical application of the indane derivatives as MAO-B inhibitors.
Background
Parkinson's Disease (PD) is a common degenerative disease of the nervous system, with a second incidence among geriatric diseases. The prevalence rate of PD in people over 65 years old in China is about 1.7%. Displaying the medical economic report: the sales of the drugs for treating PD in China has steadily increased since 2007, and the sales of the anti-PD drugs reaches 7.62 million yuan in 2009. Day 11 of month 4 (world parkinsonian day) 2015, the international parkinsonian association's statistics show: about 200 million PD and dyskinesia patients account for nearly half of the world's total number in China. At present, no medicine can cure PD on the market, and only can relieve PD. Some drugs have safety and drug effect problems, and a safe, efficient and highly selective drug is urgently needed. Dopamine (DA) is a precursor of Noradrenaline (NA), a key neurotransmitter in the hypothalamus and pituitary gland, and is synthesized by dopaminergic neurons. The research finds that DA has a very important regulating effect on body movement, and the deficiency of dopamine can cause people to lose the ability to control muscles, and can cause involuntary tremor of hands and feet of patients or cause PD. The pathological change of PD protrusion is the degeneration and death of mesencephalic substantia nigra dopaminergic neuron, and the disease is caused by the obvious reduction of striatal DA content.
Monoamine oxidase (MAO), a flavoprotein enzyme, is present on the outer membrane of the mitochondria of many tissues and catalyzes the oxidative dehydrogenation of monoamines. MAO is divided into two subtypes, monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). DA is readily induced by MAO-B to produce hydrogen peroxide (H)2O2) And other reactive oxygen species, leading to increased oxidative stress that destroys dopamine neuron cells in the glia nigra, resulting in a decrease in DA. MAO-B inhibitors treat PD by resisting oxidative stress, reducing dopaminergic neuronal apoptosis, and reducing DA oxidation. The expression level of MAO-B is improved along with the increase of age, and the MAO-B has wide development prospect as a target for developing a drug Parkinson drug.
Until now, many small molecules with MAO-B inhibitory activity have been reported publicly, such as the first generation MAO-B inhibitor selegiline (selegiline), the second generation MAO-B inhibitor rasagiline (rasagiline), and safinamide (safinamide) marketed in europe in 2015. Although several MAO-B inhibitors have been disclosed, their application is currently limited by pharmacokinetics, etc., and there is no long-acting drug, so there is an urgent need to develop MAO-B inhibitors with improved properties such as high potency, low toxicity, pharmacokinetics, etc.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention aims to provide an indane derivative with good inhibitory activity and high selectivity on MAO-B, a synthesis method and application thereof.
The invention solves the technical problem and adopts the following technical scheme:
an indane derivative represented by the formula (1):
Figure BDA0001217358220000021
in the formula: x1is-CH3or-H; x2C, N, O or S; n1 is 0, 1,2 or 3; n2 is 0, 1,2, 3,4 or 5; r1Is composed of
Figure BDA0001217358220000022
R2is-H, -F, -Cl, -Br, -I, -CF3、-CH3、-CH2CH3、-CH(CH3)2、-Ph、-NH-CO-R3or-CO-NH-R4。
R3is-H,
Figure BDA0001217358220000023
or-CH2-R6；R4is-H, -CH3、-CH2-CH3、-CH(CH3)2、-(CH2)3-CH3-、-(CH2)2-OH or- (CH)2)3-OH；
R5is-H, -CH3or-Cl; r6is-H, -CH3-Cl, -Br, -OH or-CH2-OH。
The invention discloses a method for synthesizing indane derivatives, which is shown as the following formula:
Figure BDA0001217358220000025
firstly, synthesizing indanone derivatives by adopting a coupling reaction and a mitsunobu reaction, and then obtaining a target compound by imine synthesis and reductive amination reaction;
dissolving indanone derivatives in a solvent, adding acid for catalysis, then adding propargylamine, adding sodium acetate after reaction, and continuing to react to synthesize an imine intermediate; in the reductive amination reaction, a reducing agent is added to reduce the imine intermediate into secondary amine, and then a hydrogen chloride methanol solution is added to separate out a product, namely the target compound;
the acid catalyst is selected from p-toluenesulfonic acid, acetic acid, hydrogen chloride methanol solution;
the solvent is selected from dichloromethane, toluene, tetrahydrofuran, methanol, etc.;
the reaction temperature of imine synthesis and reductive amination is controlled between 10 ℃ and 40 ℃, and 20 ℃ to 30 ℃ is preferred; the preferable time of the imine synthesis reaction is 10-15 hours, and the preferable time of the reductive amination is 3-6 hours. Propargylamine is currently used for steaming, methylene dichloride is subjected to dehydration treatment, and the mass fraction of a hydrogen chloride methanol solution (methanol (hydrogen chloride)) is 10-20%.
The indane derivative obtained by the invention can be used as a MAO-B inhibitor.
The invention has the beneficial effects that: the invention provides a new indane derivative which has good inhibitory activity and high selectivity on MAO-B.
Detailed Description
The present invention is further illustrated by the following examples.
The structures of the compounds in the following examples were determined by Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). NMR shifts are given in parts per million (ppm). NMR was measured using a VNMRS600 Nuclear magnetic Analyzer, Agilent, USA, using deuterated chloroform (CDCl)3) Deuterated dimethyl sulfoxide,Deuterated acetone with internal standard Tetramethylsilane (TMS). MS was measured using an ACQUITYUPLC LCT Premier XE (ESI) mass spectrometer.
The thin layer chromatography silica gel plate is Qingdao GF254 silica gel plate with specification of 0.15mm-0.2mm, and the thin layer chromatography separation and purification product adopts specification of 0.4mm-0.5 mm. The column chromatography separation generally adopts 200-300-mesh silica gel as a carrier.
The starting materials for the following examples were all purchased from the market.
In the following examples, the reaction temperature was room temperature and the reaction solvent was methylene chloride, unless otherwise specified.
Example 1,4- (2-Phenoxyethoxy) -N-propargyl-1-aminoindan
The target product of this example has the following structural formula:
Figure BDA0001217358220000031
the synthetic route is as follows:
first, 4- (2-phenoxyethoxy) -1-indanone
Dissolving 4-hydroxy-1-indanone 1a (5g, 33.78mmol) in 70mL acetonitrile, adding potassium carbonate (8g, 57.9mmol), dropwise adding phenoxyethyl bromide (8g, 40mmol), stirring at 85 ℃ for reaction for 4h, cooling the reaction solution to room temperature after the reaction is completed, carrying out suction filtration, concentrating the filtrate under reduced pressure to obtain a black oily substance, adding 100mL ethyl acetate for dissolution, carrying out spin-drying and sample mixing, and carrying out column chromatography (petroleum ether: ethyl acetate ═ 10: 1) separation and purification to obtain an intermediate product 1b (6.39g, 23.85mmol, white solid, yield 70.6%) which is directly put into the next step.
1H NMR(600MHz,cdcl3)δ7.38(d,J＝7.5Hz,1H),7.34(t,J＝7.8Hz,1H),7.31(t,J＝7.9Hz,2H),7.09(d,J＝7.7Hz,1H),7.00(d,J＝7.1Hz,1H),6.97(d,J＝8.2Hz,2H),4.44–4.41(m,2H),4.39(dd,J＝5.4,3.5Hz,2H),3.06–3.01(m,2H),2.69–2.65(m,2H).
The second step, 4- (2-phenoxyethoxy) -N-propargyl-1-aminoindan
Intermediate 1b (5g, 22mmol) and acetic acid (1mL) were dissolved in dichloromethane, propargylamine (1.4mL, 24mmol) was added and reacted for 3h, then sodium acetate (2g, 25mmol) was added and reacted for 11h, and the reaction solution was filtered with suction. Adding sodium acetate (0.6g, 10mmol) into the filtrate, adding sodium triacetoxyborohydride (5.2g, 25mmol) into the filtrate in batches (1040mg multiplied by 5) under ice bath, reacting at 25 ℃ for 4 hours, then carrying out suction filtration, adding a hydrogen chloride methanol solution (14mL) into the filtrate to adjust the pH value to be less than 2, separating out white solid, recrystallizing the white solid, dissolving the white solid with methanol, concentrating, adding ethyl acetate to separate out the white solid, carrying out suction filtration, and carrying out vacuum drying to obtain the white solid, namely the target product.
1H NMR(600MHz,dmso)δ10.13(s,2H),7.45–7.13(m,4H),6.99(dd,J＝47.1,15.4Hz,4H),4.76(s,1H),4.32(d,J＝15.3Hz,4H),3.84(dd,J＝38.6,15.8Hz,2H),3.69(d,J＝17.7Hz,1H),2.99(s,1H),2.73(s,1H),2.36(s,1H),2.23(s,1H).
Example 2, 4-chloro-N- (3-2- (1- (propargyl-1-aminoindan) -4-yloxy) -ethoxyphenyl) -benzamide
The target product of this example has the following structural formula:
Figure BDA0001217358220000041
the synthetic route is as follows:
Figure BDA0001217358220000042
first step, 4-chloro-N- (3- (3-hydroxy) -ethoxyphenyl) benzamide
The compounds p-chlorobenzoic acid (586mg, 3.76mmol), triethylamine (578mL, 4.18mmol) and HBTU (1580mg, 4.18mmol) were dissolved in dichloromethane, stirred for 15min, then 3-aminophenylethanol 2a (286mg, 2.09mmol) was added, reaction was carried out at 25 ℃ for 12 hours, after completion of the reaction, the reaction mixture was concentrated under reduced pressure, distilled water was added, ethyl acetate was extracted (50mL × 2), the organic phases were washed with saturated brine, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate ═ 3: 1) to obtain intermediate 2b (intermediate 2 b) (282.5mg, 0.099mmol, white solid, yield 49.6%).
1H NMR(600MHz,cdcl3)δ7.83(s,1H),7.80(d,J＝8.4Hz,2H),7.54(s,1H),7.46(t,J＝10.2Hz,1H),7.31(t,J＝7.8Hz,3H),7.03(d,J＝7.6Hz,1H),3.88(t,J＝6.5Hz,2H),2.87(t,J＝6.5Hz,2H).
Second, 4-chloro-N- (3- (2- (1-keto-2, 3-dihydro-1H-indan) -4-yloxy) -ethoxyphenyl) benzamide
Compound 2b (555mg, 2.09mmol), triphenylphosphine (976mg, 3.76mmol) and 4-hydroxy-1-indanone (556mg, 3.76mmol) were dissolved in anhydrous tetrahydrofuran, di-tert-butyl azodicarboxylate (864mg, 3.76mmol) was added in portions to react at 25 ℃ for 12 hours, after the reaction was completed, the reaction mixture was concentrated under reduced pressure, distilled water was added, ethyl acetate was extracted (50mL × 2), the saturated brine was washed, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate ═ 5: 1) to give intermediate 2c (546mg, 1.35mmol, white solid, yield 60%).
1H NMR(600MHz,cdcl3)δ7.81(d,J＝8.3Hz,1H),7.74(s,1H),7.47(d,J＝8.2Hz,1H),7.39(d,J＝8.0Hz,1H),7.31(dt,J＝15.6,7.7Hz,1H),7.12(d,J＝7.5Hz,1H),7.00(d,J＝7.6Hz,1H),4.28(t,J＝6.7Hz,1H),3.16(t,J＝6.7Hz,1H),3.06–2.96(m,1H),2.68–2.61(m,1H).
The third step, 4-chloro-N- (3-2- (1- (propargyl-1-aminoindan) -4-yloxy) -ethoxyphenyl) -benzamide
Dissolving a compound 2c (1g, 2.48mmol) and acetic acid (0.25mL) in dichloromethane, adding propargylamine (0.45mL, 2.5mmol) to react for 13h, filtering the reaction solution after the reaction is finished, adding sodium acetate (0.9g, 15mmol) and sodium triacetoxyborohydride (496g, 2.48mmol) to the filtrate, stirring to react for 3h, filtering, adding methanol (hydrogen chloride) (4mL) to the filtrate to adjust the pH to be less than 2, separating out white solids, recrystallizing the white solids, dissolving the white solids with methanol, concentrating, adding ethyl acetate to separate out white solids, filtering, and drying in vacuum to obtain white solids, namely the target product.
1H NMR(600MHz,dmso)δ9.85(s,2H),7.98(d,J＝8.3Hz,2H),7.75(s,1H),7.59(t,J＝10.2Hz,3H),7.29–7.21(m,3H),7.06(d,J＝7.5Hz,1H),7.02–6.95(m,1H),4.75(s,2H),4.21(t,J＝6.4Hz,4H),3.71(s,1H),2.98–2.91(m,2H),2.77–2.68(m,1H),2.36(dd,J＝14.2,6.9Hz,1H),2.23–2.13(m,1H).
Example 3, 4-2- (naphthyl-1-yloxy) -ethoxy-N-propargyl 1-aminoindan
The target product of this example has the following structural formula:
Figure BDA0001217358220000051
the synthetic route is as follows:
first, the compounds bromonaphthalene (2mL, 20.9mmol), anhydrous ketone chloride (100mg, 0.75mmol) and potassium carbonate (3588mg, 26mmol) were dissolved in ethylene glycol (40mL), reacted at 100 ℃ for 12 hours, cooled to room temperature after completion of the reaction, the reaction mixture was concentrated under reduced pressure, distilled water was added, ethyl acetate was extracted (50mL × 2), washed with saturated saline, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by column chromatography (petroleum ether: ethyl acetate ═ 5: 1) to obtain intermediate 3a (950mg, 12mmol, pale yellow liquid, yield 60%).
1H NMR(600MHz,cdcl3)δ8.39(t,J＝8.2Hz,1H),7.86(dd,J＝15.6,8.6Hz,1H),7.53(ddd,J＝11.1,10.0,5.6Hz,3H),7.40(t,J＝7.9Hz,1H),6.75(d,J＝7.6Hz,1H),4.17–4.13(m,2H),4.08–4.04(m,2H),3.25(s,1H).
And a second step of dissolving the compound 3a (600mg, 7.5mmol), triphenylphosphine (2360mg, 9mmol) and 4-hydroxy-1-indanone (1332mg, 9mmol) in anhydrous tetrahydrofuran, adding di-tert-butyl azodicarboxylate (2070mg, 9mmol) in portions, reacting at 25 ℃ for 12 hours, concentrating the reaction solution under reduced pressure after the reaction is finished, adding distilled water, extracting with ethyl acetate (50 mL. times.2), washing with saturated saline, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate ═ 8: 1) to obtain an intermediate 3b (1025mg, 3.8mmol, white solid, yield 49.6%).
1H NMR(600MHz,cdcl3)δ8.21(d,J＝8.4Hz,1H),7.81(d,J＝8.1Hz,1H),7.46(ddd,J＝22.5,15.2,7.1Hz,3H),7.41–7.34(m,3H),7.16(d,J＝7.2Hz,1H),6.90(d,J＝7.6Hz,1H),4.57(s,4H),3.15–2.84(m,2H),2.73–2.52(m,2H).
And thirdly, dissolving the compound 3b (2g, 6.67mmol) and acetic acid (0.3mL) in dichloromethane, adding propargylamine (0.8mL, 8mmol) and sodium acetate (0.9g, 15mmol) to react for 13h, filtering the reaction solution after the reaction is finished, adding sodium triacetoxyborohydride (1.65g, 8mmol) into the filtrate, stirring to react for 3.5h, filtering, adding methanol (hydrogen chloride) (6mL) into the filtrate to adjust the pH to be less than 2, separating out white solids, recrystallizing the white solids, dissolving with methanol, concentrating, adding ethyl acetate to separate out the white solids, filtering, and drying in vacuum to obtain the white solids, namely the target product.
1H NMR(600MHz,dmso)δ10.24(s,2H),7.93(dd,J＝16.8,8.2Hz,1H),7.93–7.86(m,3H),7.55(d,J＝8.4Hz,1H),7.53–7.44(m,2H),7.36–7.27(m,1H),7.25–7.16(m,1H),7.07(d,J＝8.1Hz,1H),4.77(dd,J＝7.5,4.3Hz,1H),4.57(s,4H),3.91–3.81(m,2H),3.72(d,J＝0.7Hz,1H),3.14–3.07(m,1H),2.91–2.77(m,1H),2.39(td,J＝14.5,7.9Hz,1H),2.31–2.23(m,1H).
Example 4, 4-benzyloxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
the synthetic route is as follows:
Figure BDA0001217358220000062
first, 4-benzyloxy-2, 3-dihydro-1H-indan-1-one
Dissolving the compound 4-hydroxy 1-indanone (1g, 6.75mmol), benzyl bromide (1.18g, 7.42mmol) and potassium carbonate (1.2g, 8mmol) in acetone, reacting at 85 ℃ for 5h, cooling to room temperature after the reaction is finished, suction filtering the reaction solution, concentrating the filtrate under reduced pressure, adding distilled water, extracting with ethyl acetate (50mL × 2), washing with saturated saline, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate ═ 12: 1) to obtain an intermediate 4a (1.2g, 5.4mmol, white solid, yield 80%).
1H NMR(600MHz,dmso)δ7.47(d,J＝7.5Hz,2H),7.38(dd,J＝14.0,6.4Hz,2H),7.35(d,J＝7.6Hz,1H),7.32(t,J＝7.4Hz,1H),7.29(d,J＝7.9Hz,1H),7.20(d,J＝7.5Hz,1H),5.22(s,2H),3.07–2.90(m,2H),2.66–2.54(m,2H).
Second, 4-benzyloxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Compound 4a (0.95g, 4mmol) and acetic acid (0.2mL) were dissolved in dichloromethane, propargylamine (0.35mL, 3.1mmol) was added, and after 2h reaction, sodium acetate (0.6g, 10mmol) was added and the reaction was carried out for 12 h. And (2) carrying out suction filtration on the reaction liquid, adding sodium acetate (0.2g, 3.3mmol) into the filtrate, adding sodium triacetoxyborohydride (1g, 3mmol) into the filtrate in batches (200mg multiplied by 5) under ice bath, carrying out suction filtration after reacting for 4h at 25 ℃, adding methanol (hydrogen chloride) (10mL) into the filtrate to adjust the pH value to be less than 2, separating out white solid, recrystallizing the white solid, dissolving the white solid with methanol, concentrating, adding ethyl acetate to separate out the white solid, carrying out suction filtration, and carrying out vacuum drying to obtain the white solid, namely the target product.
1H NMR(600MHz,dmso)δ8.73(s,2H),7.44(d,J＝7.4Hz,2H),7.41–7.34(m,3H),7.32(t,J＝7.3Hz,1H),7.26–7.18(m,1H),7.04(d,J＝8.1Hz,1H),5.15(s,2H),4.78(dd,J＝7.7,4.3Hz,1H),3.92–3.79(m,2H),3.74(t,J＝2.4Hz,1H),3.12–3.01(m,1H),2.84–2.75(m,1H),2.40(td,J＝14.2,8.3Hz,1H),2.27(dq,J＝8.7,4.6Hz,1H).
Example 5, 4- ((4-methylbenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000071
the synthetic route is as follows:
Figure BDA0001217358220000072
first step, 4- ((4-methylbenzyl) oxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide was changed to 4-methylbenzyl bromide and the other conditions were unchanged.
1H NMR(600MHz,dmso)δ7.25(d,J＝7.3Hz,3H),7.18(dd,J＝16.9,9.2Hz,1H),7.06(d,J＝7.5Hz,2H),7.01(d,J＝8.0Hz,1H),5.07(s,2H),3.07–2.68(m,2H),2.70–2.52(m,2H).
Second, 4- ((4-methylbenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 5a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ10.09(s,2H),7.30(d,J＝7.4Hz,3H),7.21(dd,J＝16.9,9.2Hz,1H),7.16(d,J＝7.5Hz,2H),7.01(d,J＝8.0Hz,1H),5.07(s,2H),4.76(s,1H),3.84(dd,J＝38.9,16.5Hz,2H),3.69(d,J＝26.3Hz,1H),3.06–2.97(m,1H),2.76(dd,J＝14.9,6.3Hz,1H),2.27(s,3H),2.25–2.19(m,1H).
Example 6, 4- ((3-chlorobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000081
the synthetic route is as follows:
Figure BDA0001217358220000082
first step, 4- ((3-chlorobenzyl) oxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide was changed to 3-chlorobenzyl bromide without changing other conditions.
1H NMR(600MHz,dmso)δ7.52(s,1H),7.44–7.31(m,4H),7.26(d,J＝7.9Hz,1H),7.21(t,J＝10.7Hz,1H),5.23(s,2H),3.07–2.68(m,2H),2.70–2.52(m,2H).
Second, 4- ((3-chlorobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 6a, and other conditions were not changed.
1H NMR(600MHz,dmso)δ10.00(d,J＝140.2Hz,2H),7.48(s,1H),7.44–7.21(m,5H),7.01(dd,J＝7.8,3.7Hz,1H),5.16(d,J＝2.0Hz,2H),4.78(dd,J＝7.4,4.2Hz,1H),3.95–3.77(m,2H),3.71(t,J＝2.5Hz,1H),3.05(dd,J＝15.8,7.1Hz,1H),2.87–2.73(m,1H),2.44–2.34(m,1H),2.24(s,1H).
Example 7, 4- ((3-Fluorobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000091
the synthetic route is as follows:
Figure BDA0001217358220000092
first step, 4- ((3-fluorobenzyl) oxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide was changed to 3-fluorobenzyl bromide and the other conditions were not changed.
1H NMR(600MHz,dmso)δ7.52(s,1H),7.44–7.31(m,4H),7.26(d,J＝7.9Hz,1H),7.21(t,J＝10.7Hz,1H),5.23(s,2H),3.07–2.68(m,2H),2.70–2.52(m,2H).
Second, 4- ((3-fluorobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 7a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ9.99(s,2H),7.47–7.37(m,1H),7.32–7.21(m,4H),7.13(td,J＝8.8,2.4Hz,1H),7.01(d,J＝8.0Hz,1H),5.17(s,2H),4.78(dd,J＝7.6,4.2Hz,1H),3.87(q,J＝16.6Hz,2H),3.75–3.66(m,1H),3.13–2.93(m,1H),2.88–2.76(m,1H),2.41(td,J＝14.6,7.9Hz,1H),2.28–2.14(m,1H).
Example 8, 4- ((3, 4-difluorobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000093
the synthetic route is as follows:
Figure BDA0001217358220000094
first step, 4- ((3, 4-difluorobenzyl) oxy)) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide was changed to 3, 4-difluorobenzyl bromide, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ7.52–7.41(m,2H),7.29(dd,J＝6.8,2.4Hz,2H),7.24(t,J＝7.8Hz,1H),7.01(d,J＝8.0Hz,1H),5.13(s,2H),3.07–2.68(m,2H),2.70–2.52(m,2H).
Second, 4- ((3, 4-difluorobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 8a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ9.94(s,2H),7.52–7.41(m,2H),7.29(dd,J＝6.8,2.4Hz,2H),7.24(t,J＝7.8Hz,1H),7.01(d,J＝8.0Hz,1H),5.13(s,2H),4.77(s,1H),3.88(q,J＝16.6Hz,2H),3.72(s,1H),3.09–2.96(m,1H),2.81(ddd,J＝16.2,8.8,4.8Hz,1H),2.40(td,J＝14.2,8.4Hz,1H),2.29–2.17(m,1H).
Example 9, 4- (Naphthalen-2-ylmethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000101
the synthetic route is as follows:
Figure BDA0001217358220000102
first step, 4- (naphthalen-2-ylmethoxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide was replaced with 2-bromomethylnaphthalene, and the other conditions were unchanged.
1H NMR(600MHz,dmso)δ7.93(dd,J＝16.8,8.2Hz,1H),7.93–7.86(m,3H),7.55(d,J＝8.4Hz,1H),7.53–7.44(m,2H),7.36–7.27(m,1H),7.25–7.16(m,1H),7.07(d,J＝8.1Hz,1H),5.23(s,2H),3.07–2.68(m,2H),2.70–2.52(m,2H).
Second, 4- (naphthalen-2-ylmethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 9a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ10.24(s,2H),7.93(dd,J＝16.8,8.2Hz,1H),7.93–7.86(m,3H),7.55(d,J＝8.4Hz,1H),7.53–7.44(m,2H),7.36–7.27(m,1H),7.25–7.16(m,1H),7.07(d,J＝8.1Hz,1H),5.29(s,2H),4.77(dd,J＝7.5,4.3Hz,1H),3.91–3.81(m,2H),3.72(d,J＝0.7Hz,1H),3.14–3.07(m,1H),2.91–2.77(m,1H),2.39(td,J＝14.5,7.9Hz,1H),2.31–2.23(m,1H).
Example 10, 4- ((4-Fluorobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000111
the synthetic route is as follows:
Figure BDA0001217358220000112
first step, 4- ((4-fluorobenzyl) oxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide was changed to 4-fluorobenzyl bromide and the other conditions were not changed.
1H NMR(600MHz,dmso)δ7.41(d,J＝7.4Hz,2H),7.38–7.31(m,3H),7.29(t,J＝7.3Hz,1H),7.21(t,J＝7.8Hz,1H),7.01(d,J＝8.1Hz,1H),5.12(s,2H),3.14–3.07(m,2H),2.73–2.65(m,2H).
Second, 4- ((4-fluorobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 10a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ9.21–8.04(m,2H),7.41(d,J＝7.4Hz,2H),7.38–7.31(m,3H),7.29(t,J＝7.3Hz,1H),7.21(t,J＝7.8Hz,1H),7.01(d,J＝8.1Hz,1H),5.12(s,2H),4.75(dd,J＝7.7,4.3Hz,1H),3.81(tt,J＝23.4,4.3Hz,2H),3.71(t,J＝2.4Hz,1H),3.08–2.99(m,1H),2.82–2.71(m,1H),2.37(td,J＝14.2,8.3Hz,1H),2.24(dq,J＝8.7,4.6Hz,1H).
Example 11, 4- ((4-trifluoromethylbenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000113
the synthetic route is as follows:
Figure BDA0001217358220000114
first step, 4- ((4-trifluoromethylbenzyl) oxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide was changed to 4-trifluoromethyl benzyl bromide, and the other conditions were not changed.
1H NMR(600MHz,cdcl3)δ7.66(d,J＝8.1Hz,2H),7.57(d,J＝8.0Hz,2H),7.38(d,J＝7.6Hz,1H),7.32(t,J＝7.7Hz,1H),7.05(d,J＝7.8Hz,1H),5.22(s,2H),3.14–3.07(m,2H),2.73–2.65(m,2H).
Second, 4- ((4-trifluoromethylbenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 11a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ8.76(s,2H),7.50–7.43(m,2H),7.32(d,J＝7.6Hz,1H),7.27–7.12(m,3H),7.01(d,J＝8.1Hz,1H),5.15–4.96(m,2H),4.75(dd,J＝7.7,4.4Hz,1H),3.88–3.73(m,2H),3.67(d,J＝2.3Hz,1H),3.09–2.95(m,1H),2.76(ddd,J＝13.5,8.4,4.6Hz,1H),2.37(td,J＝14.3,7.6Hz,1H),2.29–2.17(m,1H).
Example 12, 4- ((3-bromobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000121
the synthetic route is as follows:
Figure BDA0001217358220000122
first step, 4- ((3-bromobenzyl) oxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide (1.18g, 7.42mmol) was replaced with 3-bromobenzyl bromide (1.28g, 7.42mmol), and the other conditions were unchanged.
1H NMR(600MHz,dmso)δ7.66(s,1H),7.50(d,J＝7.9Hz,1H),7.46(d,J＝7.6Hz,1H),7.34(ddd,J＝7.7,5.2,2.8Hz,2H),7.25(dd,J＝7.9,2.6Hz,1H),7.20(d,J＝7.5Hz,1H),5.21(d,J＝3.2Hz,2H),2.97(d,J＝5.1Hz,2H),2.62–2.55(m,2H).
Second, 4- ((3-bromobenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 12a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ10.07(s,2H),7.62(s,1H),7.50(d,J＝7.9Hz,1H),7.43(d,J＝7.6Hz,1H),7.36–7.29(m,2H),7.22(dd,J＝23.1,15.3Hz,1H),7.00(d,J＝8.1Hz,1H),5.15(s,J＝13.3Hz,2H),4.77(dd,J＝7.4,4.3Hz,1H),3.85(dd,J＝37.7,16.7Hz,2H),3.74(d,J＝25.1Hz,1H),3.13–2.90(m,1H),2.86–2.69(m,1H),2.39(td,J＝14.4,8.2Hz,1H),2.29–2.19(m,1H).
Example 13, 4- ((3-methylbenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000131
the synthetic route is as follows:
first step, 4- ((3-methylbenzyl) oxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 4, benzyl bromide (1.18g, 7.42mmol) was replaced with 3-methylbenzyl bromide (1.28g, 7.42mmol), and the other conditions were unchanged.
1H NMR(600MHz,dmso)δ7.66(s,1H),7.50(d,J＝7.9Hz,1H),7.46(d,J＝7.6Hz,1H),7.34(ddd,J＝7.7,5.2,2.8Hz,2H),7.25(dd,J＝7.9,2.6Hz,1H),7.20(d,J＝7.5Hz,1H),5.21(d,J＝3.2Hz,2H),2.97(d,J＝5.1Hz,2H),2.62–2.55(m,2H),2.1(s,3H).
Second, 4- ((3-methylbenzyl) oxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to compound 13a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ8.73(s,2H),7.44(d,J＝7.4Hz,2H),7.41–7.34(m,3H),7.32(t,J＝7.3Hz,1H),7.26–7.18(m,1H),7.04(d,J＝8.1Hz,1H),5.15(s,2H),4.78(dd,J＝7.7,4.3Hz,1H),3.92–3.79(m,2H),3.74(t,J＝2.4Hz,1H),3.12–3.01(m,1H),2.84–2.75(m,1H),2.40(td,J＝14.2,8.3Hz,1H),2.27(dq,J＝8.7,4.6Hz,1H).
Example 14, 4-Phenylethoxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000133
the synthetic route is as follows:
Figure BDA0001217358220000134
first step, 4-phenethyloxy-2, 3-dihydro-1H-indan-1-one
Dissolving the compound 4-hydroxy-1-indanone (1g, 6.75mmol), phenethyl alcohol (893.8mg, 8.78mmol) and triphenyl phosphorus (2.28g, 8.78mmol) in tetrahydrofuran, adding di-tert-butyl azodicarboxylate (2.02g, 8.78mmol), reacting at 30 ℃ for 12 hours, concentrating the reaction solution under reduced pressure after the reaction is finished, adding distilled water, extracting with ethyl acetate (50mL × 2), washing with saturated saline, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate ═ 8: 1) to obtain an intermediate 14a (1.02g, 4.44mmol, white solid, yield 65.8%).
1H NMR(600MHz,cdcl3)δ7.32(dq,J＝15.3,7.6Hz,6H),7.26(t,J＝7.0Hz,1H),7.00(d,J＝7.7Hz,1H),7.00(d,J＝7.7Hz,1H),4.26(t,J＝6.8Hz,2H),3.15(t,J＝6.8Hz,2H),3.02(dd,J＝14.7,9.2Hz,2H),2.73–2.54(m,2H).
Second, 4-Phenylethoxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Compound 14a (1.42g, 4.4mmol) and acetic acid (0.2mL) were dissolved in dichloromethane, propargylamine (0.25mL, 4.6mmol) was added, and after 1h reaction, sodium acetate (0.6g, 10mmol) was added and the reaction was carried out for 13 h. And (2) carrying out suction filtration on the reaction liquid, adding sodium acetate (0.2g, 3.3mmol) into the filtrate, adding sodium triacetoxyborohydride (1g, 3mmol) into the filtrate in batches (200mg multiplied by 5) under ice bath, carrying out suction filtration after reacting for 4h at 25 ℃, adding methanol (hydrogen chloride) (6mL) into the filtrate to adjust the pH value to be less than 2, separating out white solid, recrystallizing the white solid, dissolving the white solid with methanol, concentrating, adding ethyl acetate to separate out the white solid, carrying out suction filtration, and carrying out vacuum drying to obtain the white solid, namely the target product.
1H NMR(600MHz,dmso)δ10.08(d,J＝50.4Hz,2H),7.34–7.24(m,5H),7.20(ddd,J＝9.9,8.3,4.9Hz,2H),6.96(dd,J＝8.0,3.5Hz,1H),4.74(dd,J＝7.5,4.1Hz,1H),4.18(t,J＝6.6Hz,2H),3.91–3.75(m,2H),3.74–3.65(m,1H),3.00(t,J＝6.6Hz,2H),2.98–2.90(m,1H),2.69(ddd,J＝13.8,8.6,4.5Hz,1H),2.41–2.27(m,1H),2.21(ddd,J＝18.2,8.5,4.4Hz,1H).
Example 15 4- (3-Chloroethyl) oxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000141
the synthetic route is as follows:
first, 4- (3-Chloroethyl) oxy-2, 3-dihydro-1H-indan-1-one
Referring to example 14, the phenethyl alcohol was changed to 3-chlorophenylethanol, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ7.41(s,1H),7.36–7.22(m,5H),7.17(d,J＝7.5Hz,1H),4.27(t,J＝6.5Hz,1H),3.06(t,J＝6.5Hz,1H),2.87–2.80(m,1H),2.61–2.52(m,1H).
Second, 4- (3-Chloroethyl) oxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 14, 14a was changed to 15a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ10.08(d,J＝4.4Hz,2H),7.39(s,1H),7.32(d,J＝7.7Hz,1H),7.30(d,J＝3.2Hz,1H),7.28(d,J＝6.6Hz,1H),7.27–7.25(m,1H),7.24–7.20(m,1H),6.97(t,J＝6.9Hz,1H),4.73(d,J＝28.8Hz,1H),4.19(t,J＝6.5Hz,2H),3.90–3.77(m,2H),3.69(dd,J＝7.2,4.8Hz,1H),3.02(t,J＝6.4Hz,2H),3.00–2.89(m,1H),2.68(ddd,J＝16.2,8.8,4.6Hz,1H),2.37(td,J＝14.4,8.3Hz,1H),2.27–2.19(m,1H).
Example 16, 4- (4-Chloroethyl) oxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000151
the synthetic route is as follows:
Figure BDA0001217358220000152
first, 4- (4-Chloroethyl) oxy-2, 3-dihydro-1H-indan-1-one
Referring to example 14, the phenethyl alcohol was changed to 4-chlorophenylethanol, and the other conditions were not changed.
1H NMR(600MHz,cdcl3)δ7.33(d,J＝7.4Hz,1H),7.32–7.27(m,1H),7.23(d,J＝8.4Hz,1H),6.98(s,1H),4.22(t,J＝6.5Hz,1H),3.11(t,J＝6.5Hz,1H),3.03–2.88(m,1H),2.72–2.55(m,1H).
Second, 4- (4-Chloroethyl) oxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 14, 14a was changed to 16a, and the other conditions were not changed.
1H NMR(600MHz,dmso)δ9.87(s,2H),7.37–7.34(m,2H),7.33(d,J＝8.7Hz,2H),7.24(q,J＝7.3Hz,2H),7.04–6.92(m,1H),4.75(dd,J＝7.6,3.9Hz,1H),4.19(t,J＝6.4Hz,2H),3.95–3.81(m,2H),3.71(s,1H),3.01(t,J＝6.4Hz,2H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H),2.19(s,1H).
Example 17N- (3- (2- ((1- ((propyl-2-yn-1-yl) amine) -2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
The target product of this example has the following structural formula:
Figure BDA0001217358220000161
the synthetic route is as follows:
Figure BDA0001217358220000162
first step, meta-acetaminophen
Acetic acid (0.28mL, 4.87mmol), benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) (2.4g, 6.33mmol), and triethylamine (0.88mL, 6.33mmol) were dissolved in dichloromethane and stirred for 20min, and the compound m-aminophenol (955.8mg, 6.33mmol) was added and reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated. Water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate ═ 2: 1) to give an intermediate (0.64g, 3.2mmol, white solid, yield 65.8%).
1H NMR(600MHz,dmso)δ9.76(s,1H),9.31(d,J＝2.0Hz,1H),7.16(d,J＝1.7Hz,1H),7.02(t,J＝8.0Hz,1H),6.89(d,J＝8.0Hz,1H),6.39(d,J＝8.0Hz,1H),1.99(s,3H).
Second, 4- (2-hydroxyethoxy) -2, 3-dihydro-1H-indan-1-one
Dissolving the compound 4-hydroxy-1-indanone (1g, 6.75mmol), 2-bromoethanol (1.18g, 7.42mmol) and potassium carbonate (1.6g, 12mmol) in acetonitrile, reacting at 85 ℃ for 7h, cooling to room temperature after the reaction is finished, suction-filtering the reaction solution, concentrating the filtrate under reduced pressure, adding distilled water, extracting with ethyl acetate (50 mL. times.2), washing with saturated saline, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate 4: 1) to obtain intermediate 17b (1.1g, 5.4mmol, white solid, yield 80%).
1H NMR(600MHz,dmso)δ7.37(t,J＝7.7Hz,1H),7.24(d,J＝6.7Hz,1H),7.20(d,J＝7.5Hz,1H),4.90(t,J＝5.5Hz,1H),4.11(t,J＝4.9Hz,1H),3.76(q,J＝5.1Hz,1H),3.00–2.94(m,1H),2.61(dd,J＝15.9,10.4Hz,1H).
The third step, N- (3- (2- ((1-keto-2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
Compound 17a (1.3g, 6.75mmol), 17b (1.73g, 8.78mmol) and triphenylphosphine (2.28g, 8.78mmol) were dissolved in tetrahydrofuran, reacted for 10min, di-tert-butyl azodicarboxylate (2.02g, 8.78mmol) was added, reacted at 30 ℃ for 12 hours, after the reaction was completed, the reaction mixture was concentrated under reduced pressure, distilled water was added, ethyl acetate was extracted (50mL × 2), the mixture was washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate ═ 4: 1) to give intermediate 17c (1.6g, 4.91mmol, white solid, yield 72.8%).
1H NMR(300MHz,DMSO)δ9.92(s,1H),7.37(dt,J＝13.5,7.7Hz,3H),7.21(dd,J＝14.5,7.5Hz,2H),7.13–7.03(m,1H),6.68(dd,J＝8.0,2.0Hz,1H),4.44(dd,J＝5.6,3.0Hz,2H),4.32(dd,J＝5.5,3.0Hz,2H),2.99–2.88(m,2H),2.61(dd,J＝6.7,4.5Hz,2H),2.03(s,3H).
The fourth step, N- (3- (2- ((1- ((propyl-2-yn-1-yl) amine) -2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
Dissolving a compound 17c (1g and 3mmol) and acetic acid (0.15mL) in dichloromethane, adding propargylamine (0.21mL and 3.6mmol) to react for 5h, adding sodium acetate (0.49g and 6mmol), continuing to react for 10h, performing suction filtration after the reaction is finished, washing a filter cake with dichloromethane, concentrating a filtrate, adding sodium acetate (0.49g and 6mmol) into the filtrate, adding sodium triacetoxyborohydride (1g and 3mmol) in batches in ice bath, stirring to react for 3h, performing suction filtration, adding methanol (hydrogen chloride) (6mL) into the filtrate to adjust the pH to be less than 2, separating out a white solid, recrystallizing the white solid, dissolving with methanol, adding ethyl acetate after concentration to separate out the white solid, performing suction filtration, and performing vacuum drying to obtain the white solid.
1H NMR(300MHz,DMSO)δ9.87(s,2H),9.92(s,1H),7.37(dt,J＝13.5,7.7Hz,3H),7.21(dd,J＝14.5,7.5Hz,2H),7.13–7.03(m,1H),6.68(dd,J＝8.0,2.0Hz,1H),4.44(dd,J＝5.6,3.0Hz,2H),4.32(dd,J＝5.5,3.0Hz,2H),4.19(t,J＝6.4Hz,2H),3.95–3.81(m,2H),3.71(s,1H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H),2.19(s,1H),2.03(s,3H).
Example 18, 2-chloro-N- (3- (2- ((1- ((propyl-2-yn-1-yl) amine) -2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
The target product of this example has the following structural formula:
Figure BDA0001217358220000171
the synthetic route is as follows:
first step, 3- (2- ((1-keto-2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) aniline
Compound 17c (4g, 12.3mmol) was dissolved in 20% hydrochloric acid, refluxed at 95 ℃ for 5h, cooled to room temperature after completion of the reaction, adjusted Ph 8-9 with aqueous sodium hydroxide solution, extracted with ethyl acetate (60mL × 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate: 3: 1) to give intermediate 18a (2.23g, 7.84mmol, white solid, yield 63.8%).
1H NMR(300MHz,DMSO)δ7.40(t,J＝7.7Hz,1H),7.36–7.27(m,1H),7.23(d,J＝7.4Hz,1H),6.91(t,J＝8.1Hz,1H),6.29–6.01(m,1H),5.07(s,1H),4.40(dd,J＝5.4,3.2Hz,1H),4.25(dd,J＝5.3,3.3Hz,1H),3.04–2.88(m,1H),2.61(dd,J＝6.7,4.6Hz,1H).
Second, 2-chloro-N- (3- (2- ((1-keto-2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
Dissolving 18a (2g, 7mmol) in dichloromethane, adding potassium carbonate, stirring, slowly adding chloroacetyl chloride (0.75mL, 10mmol) in ice bath, reacting at room temperature for 6h, filtering after the reaction is finished, and washing a filter cake with dichloromethane. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate: 6: 1) to give intermediate 18b (1.91g, 5.32mmol, white solid, yield 76%).
1H NMR(600MHz,cdcl3)δ8.22(s,1H),7.40(t,J＝2.2Hz,1H),7.38(d,J＝7.2Hz,1H),7.34(t,J＝7.7Hz,1H),7.29–7.26(m,1H),7.11–7.06(m,1H),7.02(dd,J＝8.0,1.3Hz,1H),6.78(dd,J＝8.2,2.1Hz,1H),4.43–4.38(m,4H),4.19(s,2H),3.05–3.02(m,2H),2.68–2.65(m,2H).
The third step, 2-chloro-N- (3- (2- ((1- ((propyl-2-yn-1-yl) amine) -2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
Compound 18b (1.3g, 3.6mmol) and acetic acid (0.1mL) were dissolved in dichloromethane, propargylamine (0.25mL, 4.6mmol) was added, and after 2h reaction, sodium acetate (0.5g, 6.3mmol) was added and the reaction was carried out for 13 h. And (2) carrying out suction filtration on the reaction liquid, adding sodium acetate (0.5g, 6.3mmol) into the filtrate, adding sodium triacetoxyborohydride (1g, 3mmol) into the filtrate in batches (200mg multiplied by 5) under ice bath, reacting at 25 ℃ for 4h, carrying out suction filtration, adding methanol (hydrogen chloride) (6mL) into the filtrate to adjust the pH value to be less than 2, separating out a white solid, recrystallizing the white solid, dissolving the white solid with methanol, concentrating, adding ethyl acetate to separate out the white solid, carrying out suction filtration, and carrying out vacuum drying to obtain the white solid, namely the target product.
1H NMR(600MHz,cdcl3)δ9.87(s,2H),8.22(s,1H),7.40(t,J＝2.2Hz,1H),7.38(d,J＝7.2Hz,1H),7.34(t,J＝7.7Hz,1H),7.29–7.26(m,1H),7.11–7.06(m,1H),7.02(dd,J＝8.0,1.3Hz,1H),6.78(dd,J＝8.2,2.1Hz,1H),4.43–4.38(m,2H),4.19(m,3H),3.95–3.81(m,2H),3.71(s,1H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H),2.19(m,1H).
Example 19, 4- (3-Phenoxypropyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000191
the synthetic route is as follows:
Figure BDA0001217358220000192
first step, 4- (3-Bromopropoxy) -2, 3-dihydro-1H-indan-1-one
Dissolving a compound 4-hydroxy-1-indanone 1a (1g, 6.75mmol), 1, 3-dibromopropane (2g, 11.7mmol) and potassium carbonate (1.28g, 8.78mmol) in acetonitrile, reacting at 80 ℃ for 8h, after the reaction is finished, carrying out suction filtration on a reaction solution, washing a filter cake with ethyl acetate, spinning the filtrate, adding ethyl acetate for dissolving, adding distilled water, extracting with ethyl acetate (50mL multiplied by 2), washing with saturated saline, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate ═ 15: 1) to obtain an intermediate 19a (1.08g, 4.05mmol), a white solid with the yield of 60%.
1H NMR(400MHz,CDCl3)δ7.35(q,J＝7.7Hz,2H),7.05(d,J＝7.3Hz,1H),4.21(t,J＝5.7Hz,2H),3.64(t,J＝6.3Hz,2H),3.11–3.00(m,2H),2.74–2.63(m,2H),2.38(dd,J＝12.0,6.0Hz,2H).
Second, 4- (3-phenoxypropyloxy) -2, 3-dihydro-1H-indan-1-one
Compound 19a (1.8g, 6.75mmol), phenol (1.5g, 8.78mmol) and potassium carbonate (1.28g, 8.78mmol) were dissolved in acetonitrile and reacted at 80 ℃ for 5h, after completion of the reaction, the reaction solution was suction filtered, the cake was washed with ethyl acetate, the filtrate was concentrated, distilled water was added, ethyl acetate was extracted (50mL × 2), the filtrate was washed with saturated saline, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and isolated and purified by column chromatography (petroleum ether: ethyl acetate ═ 10: 1) to give intermediate 19b (1.29g, 4.38mmol, white solid, yield 65%).
1H NMR(600MHz,cdcl3)δ7.35–7.26(m,3H),7.05(d,J＝7.5Hz,2H),6.95(t,J＝7.3Hz,1H),6.93–6.89(m,2H),4.26(t,J＝6.1Hz,2H),4.19(t,J＝6.0Hz,2H),3.05–3.01(m,2H),2.72–2.59(m,2H),2.32(dd,J＝12.1,6.1Hz,2H).
The third step, 4- (3-phenoxypropyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Dissolve 19b (0.8g, 2.7mmol) and 4 drops of acetic acid in dichloromethane (25mL) and add propargylamine (0.25mL, 4.6mmol) for 10 h. Adding sodium acetate (0.3g, 5mmol) and sodium triacetoxyborohydride (0.8g, 2.4mmol), stirring for reaction for 3h, performing suction filtration, adding methanol (hydrogen chloride) (3mL) into the filtrate to adjust the pH to be less than 2, separating out white solid, recrystallizing the white solid, dissolving with methanol, concentrating, adding ethyl acetate to separate out the white solid, performing suction filtration, and performing vacuum drying to obtain the white solid, namely the target product.
1H NMR(600MHz,DMSO)δ9.87(s,2H),7.35–7.26(m,3H),7.05(d,J＝7.5Hz,2H),6.95(t,J＝7.3Hz,1H),6.93–6.89(m,2H),4.26(t,J＝6.1Hz,2H),4.19(m,3H),3.95–3.81(m,2H),3.71(s,1H),3.05–3.01(m,2H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H),2.19(m,1H).
Example 20, 4- (3-Naphthalen-1-yloxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000201
the synthetic route is as follows:
Figure BDA0001217358220000202
first step, 4- (3-naphthalen-1-yloxy) propyloxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 19, phenol was changed to naphthol and other conditions were not changed.
1H NMR(600MHz,cdcl3)δ8.24(t,J＝12.0Hz,1H),7.73(dd,J＝80.5,8.2Hz,1H),7.46(ddd,J＝11.6,11.1,5.8Hz,3H),7.40–7.29(m,3H),7.06(t,J＝12.0Hz,1H),6.83(dd,J＝32.0,7.7Hz,1H),4.38(dt,J＝10.0,6.0Hz,4H),3.07–2.95(m,2H),2.73–2.62(m,2H),2.48(p,J＝6.0Hz,2H).
Second, 4- (3-naphthalen-1-yloxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, 19a was changed to 20a, and the other conditions were not changed.
1H NMR(600MHz,DMSO)δ9.87(s,2H),8.24(t,J＝12.0Hz,1H),7.73(dd,J＝80.5,8.2Hz,1H),7.46(ddd,J＝11.6,11.1,5.8Hz,3H),7.40–7.29(m,3H),7.06(t,J＝12.0Hz,1H),6.83(dd,J＝32.0,7.7Hz,1H),4.38(dt,J＝10.0,6.0Hz,4H),4.19(m,1H),3.71(s,1H),3.07–2.95(m,4H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H).
Example 21, 4- (3 (3-iodophenoxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000211
the synthetic route is as follows:
Figure BDA0001217358220000212
first step, 4- (3 (3-iodophenoxy) propyloxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 19, phenol was changed to m-iodophenol with the other conditions being unchanged.
1H NMR(400MHz,CDCl3)δ7.39–7.31(m,2H),7.28(dd,J＝12.9,4.9Hz,2H),7.04(d,J＝7.2Hz,1H),6.99(t,J＝8.0Hz,1H),6.88(d,J＝8.6Hz,1H),4.24(t,J＝6.0Hz,2H),4.16(t,J＝6.0Hz,2H),3.08–2.99(m,2H),2.74–2.62(m,2H),2.31(p,J＝6.0Hz,2H).
Second, 4- (3 (3-iodophenoxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, 19a was changed to 21a, and the other conditions were not changed.
1H NMR(400MHz,DMSO)δ9.87(s,2H),7.39–7.31(m,2H),7.28(dd,J＝12.9,4.9Hz,2H),7.04(d,J＝7.2Hz,1H),6.99(t,J＝8.0Hz,1H),6.88(d,J＝8.6Hz,1H),4.24(t,J＝6.0Hz,2H),4.19(m,1H),4.16(m,4H),3.71(s,1H),3.08–2.99(m,2H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H).
Example 22, 4- (3(3, 5-dimethyl-4-chloro-phenyloxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000221
the synthetic route is as follows:
Figure BDA0001217358220000222
first, 5- (3-Bromopropoxy) -2-chloro-1, 3-dimethylbenzene
Dissolving compound 3, 5-dimethyl-4-chlorophenol 22a (1.05g, 6.75mmol), 1, 3-dibromopropane (1.5g, 8.78mmol) and potassium carbonate (1.28g, 8.78mmol) in acetonitrile, reacting at 80 ℃ for 6 hours, after the reaction is finished, suction-filtering the reaction solution, concentrating the filtrate under reduced pressure, adding distilled water, extracting with ethyl acetate (50mL × 2), washing with saturated saline, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying by column chromatography (petroleum ether: ethyl acetate 15: 1) to obtain intermediate 22b (yellow oily substance), and directly putting the intermediate into the next step.
Second, 4- (3(3, 5-dimethyl-4 chloro-phenoxy) propyloxy) -2, 3-dihydro-1H-indan-1-one
Dissolving the compound 22b, 4-hydroxy-1-indanone (1g, 6.75mmol) and potassium carbonate (1.28g, 8.78mmol) in acetonitrile, reacting at 80 ℃ for 4 hours, after the reaction is finished, carrying out suction filtration on the reaction solution, concentrating the filtrate under reduced pressure, adding distilled water, extracting with ethyl acetate (50mL multiplied by 2), washing with saturated saline, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate ═ 10: 1) to obtain an intermediate 22c (1.6g, 5.1mmol, white solid, yield 75.8%).
1H NMR(300MHz,CDCl3)δ7.37–7.29(m,2H),7.03(dd,J＝8.2,6.6Hz,1H),6.65(s,2H),4.24(t,J＝6.0Hz,2H),4.14(t,J＝6.0Hz,2H),3.08–2.98(m,2H),2.72–2.62(m,2H),2.36–2.23(m,8H).
The third step, 4- (3(3, 5-dimethyl-4 chloro-phenyloxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, compound 19a was changed to 22a with the other conditions being unchanged.
Example 23, 4- (3 (4-ethylphenyl) oxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000231
the synthetic route is as follows:
Figure BDA0001217358220000232
first step, 4- (3 (4-ethylphenyl) oxy) propyloxy) -2, 3-dihydro-1H-indan-1-one
Referring to compound 19a, the starting phenol was changed to 4-ethylphenol, and the other conditions were unchanged.
1H NMR(600MHz,cdcl3)δ7.33(dt,J＝15.1,7.4Hz,2H),7.11(d,J＝8.4Hz,2H),7.08–7.01(m,1H),6.85(d,J＝8.5Hz,2H),4.25(t,J＝6.0Hz,2H),4.17(t,J＝6.0Hz,2H),3.04–2.99(m,2H),2.69–2.65(m,2H),2.59(q,J＝7.6Hz,2H),2.31(p,J＝6.0Hz,2H),1.20(t,J＝7.6Hz,3H).
Second, 4- (3 (4-ethylphenyl) oxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, compound 19a was changed to 23a with the other conditions being unchanged.
1H NMR(600MHz,cdcl3)δ7.33(dt,J＝15.1,7.4Hz,2H),7.11(d,J＝8.4Hz,2H),7.08–7.01(m,1H),6.85(d,J＝8.5Hz,2H),4.25(t,J＝6.0Hz,2H),4.18(m,3H),3.85(dd,J＝37.7,16.7Hz,2H),3.74(d,J＝25.1Hz,1H),3.04–2.99(m,2H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(m,3H),2.38(td,J＝14.9,7.8Hz,1H),2.19(s,1H),1.20(t,J＝7.6Hz,3H).
Example 24, 4- (3 (4-isopropylphenyl) oxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000233
the synthetic route is as follows:
first step, 4- (3 (4-isopropylphenyl) oxy)) propyloxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 19, the compound phenol was changed to 4-isopropylphenol, and other conditions were not changed.
1H NMR(600MHz,cdcl3)δ7.33(dt,J＝15.1,7.5Hz,2H),7.15(d,J＝8.5Hz,2H),7.05(d,J＝7.5Hz,1H),6.86(d,J＝8.6Hz,2H),4.25(t,J＝6.0Hz,2H),4.17(t,J＝6.0Hz,2H),3.07–2.97(m,2H),2.86(hept,J＝6.9Hz,1H),2.67(dd,J＝6.8,4.7Hz,2H),2.31(p,J＝6.0Hz,2H),1.22(d,J＝6.9Hz,6H).
Second, 4- (3 (4-isopropylphenyl) oxy) propyloxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, compound 19a was changed to 24a with the other conditions being unchanged.
1H NMR(600MHz,cdcl3)δ7.33(dt,J＝15.1,7.5Hz,2H),7.15(d,J＝8.5Hz,2H),7.05(d,J＝7.5Hz,1H),6.86(d,J＝8.6Hz,2H),4.77(dd,J＝7.4,4.3Hz,1H),4.25(t,J＝6.0Hz,2H),4.18(m,3H),3.85(dd,J＝37.7,16.7Hz,2H),3.74(d,J＝25.1Hz,1H),3.07–2.97(m,2H),2.91(dd,J＝37.2,29.0Hz,1H),2.86(hept,J＝6.9Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H),2.19(s,1H),1.22(d,J＝6.9Hz,6H).
Example 25, 2-hydroxy-N- (3- (2- ((1- ((propyl-2-yn-1-yl) amine) -2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
The target product of this example has the following structural formula:
the synthetic route is as follows:
Figure BDA0001217358220000243
first step, 2-hydroxy N- (3- (2- ((1-keto- -2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
Glycolic acid (371mg, 4.87mmol), benzotriazole-N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HBTU) (2.4g, 6.33mmol), and triethylamine (0.88mL, 6.33mmol) were dissolved in dichloromethane (30mL), stirred for 20min, and compound 18a (1804mg, 6.33mmol) was added and reacted at room temperature for 12 h. After the reaction was completed, the reaction solution was concentrated. Water was added, extraction was performed with ethyl acetate, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and isolated and purified by column chromatography (petroleum ether: ethyl acetate ═ 1: 3) to give intermediate 25a (761mg, 2.23mmol, white solid, yield 45.8%).
1H NMR(600MHz,cdcl3)δ8.22(s,1H),7.40(t,J＝2.2Hz,1H),7.38(d,J＝7.2Hz,1H),7.34(t,J＝7.7Hz,1H),7.29–7.26(m,1H),7.11–7.06(m,1H),7.02(dd,J＝8.0,1.3Hz,1H),6.78(dd,J＝8.2,2.1Hz,1H),4.43–4.38(m,4H),4.19(s,2H),3.4(m,1H),3.05–3.02(m,2H),2.68–2.65(m,2H).
Second, 2-hydroxy-N- (3- (2- ((1- ((propyl-2-yn-1-yl) amine) -2, 3-dihydro-1H-indan-4-yl) oxy) ethoxy) phenyl) acetamide
Compound 25a (2g, 5.8mmol) and acetic acid (0.3mL) were dissolved in dichloromethane (40mL) and reacted at 30 ℃ for 3h, propargylamine (0.41mL, 7.6mmol) was added for 23h, and sodium acetate (1g, 12.2mmol) was added for 11 h. And after the reaction is finished, carrying out suction filtration on the reaction liquid, washing by using dichloromethane, combining filtrates, concentrating the filtrate, adding sodium acetate (0.5g, 6.1mmol), adding sodium triacetoxyborohydride (1.27g, 6mmol) in batches, stirring for 5h for reaction, carrying out suction filtration, adding methanol (hydrogen chloride) (8mL) into the filtrate to adjust the pH to be less than 2, separating out a white solid, recrystallizing the white solid, dissolving the white solid with methanol, concentrating, adding ethyl acetate to separate out the white solid, carrying out suction filtration, and carrying out vacuum drying to obtain the white solid, namely the target product.
1H NMR(600MHz,cdcl3)δ9.87(s,2H),8.22(s,1H),7.40(t,J＝2.2Hz,1H),7.38(d,J＝7.2Hz,1H),7.34(t,J＝7.7Hz,1H),7.29–7.26(m,1H),7.11–7.06(m,1H),7.02(dd,J＝8.0,1.3Hz,1H),6.78(dd,J＝8.2,2.1Hz,1H),4.43–4.38(m,2H),4.19(m,3H),3.95–3.81(m,2H),3.71(s,1H),3.4(m,1H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H),2.19(m,1H).
Example 26, 4-benzyloxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000251
the synthetic route is as follows:
first, 4-benzyloxy-2, 3-dihydro-1H-indan-1-one
Taking the compound 4-bromo-1-indanone (1g, 4.74mmol), benzylthiol (0.77g, 6.11mmol) and Pd2(dba)3(0.522g, 0.57mmol), a ligand (cas:161265-03-8,0.549g, 0.95mmol), and cesium carbonate (2.3g, 7.1mmol) were dissolved in 1, 4-dioxane (30mL), reacted at 100 ℃ for 13 hours, after completion of the reaction, cooled to room temperature, the reaction mixture was suction-filtered, the filtrate was concentrated under reduced pressure, distilled water was added, ethyl acetate was extracted (50mL × 2), the filtrate was washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate ═ 25: 1) to obtain intermediate 26a (625mg, 2.49mmol, white solid, yield 52.65%).
1H NMR(600MHz,dmso)δ7.47(d,J＝7.5Hz,2H),7.38(dd,J＝14.0,6.4Hz,2H),7.35(d,J＝7.6Hz,1H),7.32(t,J＝7.4Hz,1H),7.29(d,J＝7.9Hz,1H),7.20(d,J＝7.5Hz,1H),4.3(s,2H),3.07–2.90(m,2H),2.66–2.54(m,2H).
Second, 4-benzyloxy-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 4, compound 4a was changed to 16a with the other conditions unchanged.
1H NMR(600MHz,dmso)δ8.73(s,2H),7.44(d,J＝7.4Hz,2H),7.41–7.34(m,3H),7.32(t,J＝7.3Hz,1H),7.26–7.18(m,1H),7.04(d,J＝8.1Hz,1H),4.78(dd,J＝7.7,4.3Hz,1H),4.32(s,2H),3.92–3.79(m,2H),3.74(t,J＝2.4Hz,1H),3.12–3.01(m,1H),2.84–2.75(m,1H),2.40(td,J＝14.2,8.3Hz,1H),2.27(dq,J＝8.7,4.6Hz,1H).
Example 27, 4- (3 (3-iodophenoxy) ethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000261
the synthetic route is as follows:
Figure BDA0001217358220000262
first, 4- (2-bromoethoxy) -1-indanone
Dissolving the compound 4-hydroxy-1-indanone (3g, 20.27mmol), 2-bromoethanol (3.3g, 26.35mmol) and triphenylphosphine (6.84g, 26.35mmol) in tetrahydrofuran, reacting for 10min, adding di-tert-butyl azodicarboxylate (6.06g, 26.35mmol), reacting at 30 ℃ for 12h, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding distilled water, extracting with ethyl acetate (50 mL. times.2), washing with saturated saline, combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate: 12: 1) to obtain intermediate 27a (4.16g, 16.37mmol, yellow viscous substance, yield 80.8%).
1H NMR(400MHz,CDCl3)δ7.35(q,J＝7.7Hz,2H),7.05(d,J＝7.3Hz,1H),4.21(t,J＝5.7Hz,2H),3.64(t,J＝6.3Hz,2H),3.11–3.00(m,2H),2.74–2.63(m,2H).
Second, 4- (2 (3-iodophenoxy) ethoxy) -2, 3-dihydro-1H-indan-1-one
Compound 27a (1.75g, 6.75mmol), m-iodophenol (1.8g, 8.78mmol) and potassium carbonate (1.28g, 8.78mmol) were dissolved in acetonitrile and reacted at 80 ℃ for 12 hours, after completion of the reaction, the reaction mixture was concentrated under reduced pressure, distilled water was added, ethyl acetate was extracted (50mL × 2), the reaction mixture was washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate ═ 15: 1) to give intermediate 27b (0.99g, 4.44mmol, white solid, yield 65.8%).
1H NMR(400MHz,CDCl3)δ7.39–7.31(m,2H),7.28(dd,J＝12.9,4.9Hz,2H),7.04(d,J＝7.2Hz,1H),6.99(t,J＝8.0Hz,1H),6.88(d,J＝8.6Hz,1H),4.24(t,J＝6.0Hz,2H),4.16(t,J＝6.0Hz,2H),3.08–2.99(m,2H),2.31(p,J＝6.0Hz,2H).
The third step, 4- (3 (3-iodophenoxy) ethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, compound 19a was changed to 27b with the other conditions being unchanged.
1H NMR(400MHz,DMSO)δ9.87(s,2H),7.39–7.31(m,2H),7.28(dd,J＝12.9,4.9Hz,2H),7.04(d,J＝7.2Hz,1H),6.99(t,J＝8.0Hz,1H),6.88(d,J＝8.6Hz,1H),4.24(t,J＝6.0Hz,2H),4.19(m,1H),4.16(m,4H),3.71(s,1H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H).
Example 28, 4- (2(3,5 dimethyl-4 chloro-phenyloxy) ethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000271
the synthetic route is as follows:
first, 5- (2-ethoxy) -2-chloro-1, 3-dimethylbenzene
Dissolving the compound 3, 5-dimethyl-4-chlorophenol 22a (1.02g, 6.75mmol), 1, 2-dibromoethane (1.65g, 8.78mmol) and potassium carbonate (1.28g, 8.78mmol) in acetonitrile, reacting at 80 ℃ for 12 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding distilled water, extracting with ethyl acetate (50mL multiplied by 2), washing with saturated saline, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, separating and purifying by column chromatography (petroleum ether: ethyl acetate ═ 15: 1) to obtain an intermediate product, namely a yellow oily substance 28a, and directly feeding the intermediate product to the next step.
Second, 4- (3(3, 5-dimethyl-4 chloro-phenoxy) propyloxy) -2, 3-dihydro-1H-indan-1-one
Dissolving compound 28a, 4-hydroxy-1-indanone (1g, 6.75mmol) and potassium carbonate (1.28g, 8.78mmol) in acetonitrile, reacting at 80 ℃ for 7 hours, after the reaction is finished, concentrating the reaction solution under reduced pressure, adding distilled water, extracting with ethyl acetate (50 mL. times.2), washing with saturated saline, combining organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate 10: 1) to obtain an intermediate product (1.4g, 4.44mmol, white solid, yield 65.8%).
1H NMR(300MHz,CDCl3)δ7.37–7.29(m,2H),7.03(dd,J＝8.2,6.6Hz,1H),6.65(s,2H),4.24(t,J＝6.0Hz,2H),4.14(t,J＝6.0Hz,2H),3.08–2.98(m,2H),2.72–2.62(m,2H),2.36–2.23(m,6H).
The third step, 4- (2(3, 5-dimethyl-4 chloro-phenoxy) ethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, compound 19a was changed to 28b and the other conditions were unchanged.
1H NMR(300MHz,CDCl3)δ9.87(s,2H),7.37–7.29(m,2H),7.03(dd,J＝8.2,6.6Hz,1H),6.65(s,2H),4.24(t,J＝6.0Hz,2H),4.19(m,1H),4.13(m,4H),3.71(s,1H),3.08–2.98(m,2H),2.91(dd,J＝37.2,29.0Hz,1H),2.72–2.62(m,3H),2.38(td,J＝14.9,7.8Hz,1H),2.36–2.23(m,7H).
Example 29, 4- (2 (4-ethylphenyl) oxy) ethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000281
the synthetic route is as follows:
Figure BDA0001217358220000282
first step, 4- (2 (4-ethylphenyl) oxy) ethoxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 27, the starting material, m-iodophenol, was changed to 4-ethylphenol, and the other conditions were not changed.
1H NMR(600MHz,cdcl3)δ7.33(dt,J＝15.1,7.4Hz,2H),7.11(d,J＝8.4Hz,2H),7.08–7.01(m,1H),6.85(d,J＝8.5Hz,2H),4.25(t,J＝6.0Hz,2H),4.17(t,J＝6.0Hz,2H),3.04–2.99(m,2H),2.69–2.65(m,2H),2.59(q,J＝7.6Hz,2H),1.20(t,J＝7.6Hz,3H).
Second, 4- (2 (4-ethylphenyl) oxy) ethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, compound 19a was changed to 29a with the other conditions being unchanged.
1H NMR(600MHz,cdcl3)δ7.33(dt,J＝15.1,7.4Hz,2H),7.11(d,J＝8.4Hz,2H),7.08–7.01(m,1H),6.85(d,J＝8.5Hz,2H),4.25(t,J＝6.0Hz,2H),4.18(m,3H),3.85(dd,J＝37.7,16.7Hz,2H),3.74(d,J＝25.1Hz,1H),3.04–2.99(m,2H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(m,1H),2.38(td,J＝14.9,7.8Hz,1H),2.19(s,1H),1.20(t,J＝7.6Hz,3H).
Example 30, 4- (2 (4-isopropylphenyl) oxy) ethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000291
the synthetic route is as follows:
Figure BDA0001217358220000292
first step, 4- (2 (4-isopropylphenyl) oxy)) ethoxy) -2, 3-dihydro-1H-indan-1-one
Referring to example 27, the starting material, m-iodophenol, was changed to 4-isopropylmethylphenol, and the other conditions were not changed.
1H NMR(600MHz,cdcl3)δ7.33(dt,J＝15.1,7.5Hz,2H),7.15(d,J＝8.5Hz,2H),7.05(d,J＝7.5Hz,1H),6.86(d,J＝8.6Hz,2H),4.25(t,J＝6.0Hz,2H),4.17(t,J＝6.0Hz,2H),3.07–2.97(m,2H),2.86(hept,J＝6.9Hz,1H),2.67(dd,J＝6.8,4.7Hz,2H),1.22(d,J＝6.9Hz,6H).
Second, 4- (2 (4-isopropylphenyl) oxy) ethoxy) -N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 19, compound 19a was changed to 30a with the other conditions being unchanged.
1H NMR(600MHz,cdcl3)δ7.33(dt,J＝15.1,7.5Hz,2H),7.15(d,J＝8.5Hz,2H),7.05(d,J＝7.5Hz,1H),6.86(d,J＝8.6Hz,2H),4.77(dd,J＝7.4,4.3Hz,1H),4.25(t,J＝6.0Hz,2H),4.18(m,3H),3.85(dd,J＝37.7,16.7Hz,2H),3.74(d,J＝25.1Hz,1H),2.91(dd,J＝37.2,29.0Hz,1H),2.86(hept,J＝6.9Hz,1H),2.68(ddd,J＝59.7,28.3,24.0Hz,1H),2.38(td,J＝14.9,7.8Hz,1H),2.19(s,1H),1.22(d,J＝6.9Hz,6H).
Example 31N- (3- (3- ((1- ((propyl-2-yn-1-yl) amine) -2, 3-dihydro-1H-indan-4-yl) oxy) propyloxy) phenyl) acetamide
The target product of this example has the following structural formula:
Figure BDA0001217358220000301
the synthetic route is as follows:
Figure BDA0001217358220000302
first step, N- (3- (3-bromopropoxy) phenyl) acetamide
Adding compound 17a (0.85g, 6.75mmol) and 1, 3-dibromoethane (1.84g, 12.78mmol) into acetonitrile, reacting at 850 ℃ for 6 hours, after the reaction is finished, carrying out suction filtration on the reaction solution, concentrating the filtrate under reduced pressure, adding distilled water, extracting with ethyl acetate (50mL multiplied by 2), washing with saturated saline, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate: 12: 1) to obtain an intermediate product, namely a yellow oily substance.
Second, N- (3- (3- ((1-keto-2, 3-dihydro-1H-indan-4-yl) oxy) propyloxy) phenyl) acetamide
Adding the compound 31a (1g, 6.75mmol) and 4-hydroxy-1-indanone (1g, 6.75mmol) into acetonitrile, reacting at 850 ℃ for 6 hours, after the reaction is finished, carrying out suction filtration on the reaction solution, concentrating the filtrate under reduced pressure, adding distilled water, extracting with ethyl acetate (50mL multiplied by 2), washing with saturated saline, combining organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying by column chromatography (petroleum ether: ethyl acetate: 12: 1) to obtain an intermediate product (1.22g, 4.44mmol, white solid, yield 55.8%).
1H NMR(300MHz,DMSO)δ9.92(s,1H),7.37(dt,J＝13.5,7.7Hz,3H),7.21(dd,J＝14.5,7.5Hz,2H),7.13–7.03(m,1H),6.68(dd,J＝8.0,2.0Hz,1H),4.44(dd,J＝5.6,3.0Hz,2H),4.32(dd,J＝5.5,3.0Hz,2H),2.99–2.88(m,2H),2.61(dd,J＝6.7,4.5Hz,2H),2.61(m,2H),2.03(s,3H).
The third step, N- (3- (3- ((1- ((propyl-2-yn-1-yl) amine) -2, 3-dihydro-1H-indan-4-yl) oxy) propyloxy) phenyl) acetamide
Compound 31b (1.3g, 4.4mmol) and acetic acid (0.2mL) were dissolved in dichloromethane and propargylamine (0.25mL, 4.6mmol) was added and reacted for 12h to 35 h. Adding sodium acetate (0.3g, 5mmol) and sodium triacetoxyborohydride (1g, 3mmol), stirring for 10h, filtering, adding methanol (hydrogen chloride) (8mL) into the filtrate to adjust the pH value to 2-3, separating out white solid, recrystallizing the white solid, dissolving with methanol, concentrating, adding ethyl acetate to separate out white solid, filtering, and vacuum drying to obtain white solid, namely the target product.
1H NMR(300MHz,DMSO)δ9.87(s,2H),9.92(s,1H),7.37(dt,J＝13.5,7.7Hz,3H),7.21(dd,J＝14.5,7.5Hz,2H),7.13–7.03(m,1H),6.68(dd,J＝8.0,2.0Hz,1H),4.44(dd,J＝5.6,3.0Hz,2H),4.32(dd,J＝5.5,3.0Hz,2H),4.19(t,J＝6.4Hz,2H),3.95–3.81(m,2H),3.71(s,1H),2.91(dd,J＝37.2,29.0Hz,1H),2.68(m,3H),2.38(td,J＝14.9,7.8Hz,1H),2.19(s,1H),2.03(s,3H).
Example 32, 4-Phenylethylsulfanyl-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
The target product of this example has the following structural formula:
Figure BDA0001217358220000311
the synthetic route is as follows:
Figure BDA0001217358220000312
the specific synthesis steps are as follows:
first step, 4-phenethylthio-2, 3-dihydro-1H-indan-1-one
Taking the compound 4-bromo-1-indanone (1g, 4.74mmol), phenethyl mercaptan (0.87g, 6.11mmol) and Pd2(dba)3(0.522g, 0.57mmol), a ligand (cas:161265-03-8,0.549g, 0.95mmol), and cesium carbonate (2.3g, 7.1mmol) were dissolved in 1, 4-dioxane (20mL), reacted at 95 ℃ to 100 ℃ for 10h to 22h, cooled to room temperature after the reaction was completed, the reaction solution was suction filtered, the filtrate was concentrated under reduced pressure, distilled water was added, ethyl acetate was extracted (50mL × 2), the mixture was washed with saturated brine, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by column chromatography (petroleum ether: ethyl acetate: 25: 1) to obtain an intermediate (503mg, 1.87mmol, white solid, yield 39.65%).
1H NMR(600MHz,cdcl3)δ7.32(dq,J＝15.3,7.6Hz,6H),7.26(t,J＝7.0Hz,1H),7.00(d,J＝7.7Hz,1H),7.00(d,J＝7.7Hz,1H),4.26(t,J＝6.8Hz,2H),3.15(t,J＝6.8Hz,2H),3.02(dd,J＝14.7,9.2Hz,2H),2.73–2.54(m,2H).
Second, 4-Phenylethylsulfanyl-N- (propyl-2-yn-1-yl) -2, 3-dihydro-1H-indan-1-amine
Referring to example 14, compound 14a was changed to 32a with the other conditions being unchanged.
1H NMR(600MHz,dmso)δ10.08(d,J＝50.4Hz,2H),7.34–7.24(m,5H),7.20(ddd,J＝9.9,8.3,4.9Hz,2H),6.96(dd,J＝8.0,3.5Hz,1H),4.74(dd,J＝7.5,4.1Hz,1H),4.18(t,J＝6.6Hz,2H),3.91–3.75(m,2H),3.74–3.65(m,1H),3.00(t,J＝6.6Hz,2H),2.98–2.90(m,1H),2.69(ddd,J＝13.8,8.6,4.5Hz,1H),2.41–2.27(m,1H),2.21(ddd,J＝18.2,8.5,4.4Hz,1H).
The inhibitory activity of the compound obtained in the above example on MAO-B was determined as follows:
using benzylamine as the substrate for MAO-B, 100mmol/L potassium phosphate buffer (pH 7.6), MAO inhibiting drug and 75. mu.L of MAO were incubated at 37 ℃ for 20min, 100. mu.L of benzylamine was added to give a total volume of 800. mu.L of MAO and benzylamine of 0.15mg/mL and 2mmol/L, respectively, and reacted for 60min, 200. mu.L of 10% HClO was added4Terminating the reaction, then adding 3mL of cyclohexane, swirling for 2min, extracting the product benzaldehyde, centrifuging for 5min, and measuring the A value at the wavelength of 242 nm. 1.00X 10 for each MAO inhibiting drug-5mmol/L、3.33×10-6mmol/L、1.11×10-6mmol/L、3.70×10-7mmol/L、1.23×10- 7mmol/L、4.12×10-8mmol/L、1.37×10-8mmol/L、4.57×10-9mmol/L、1.52×10-9mmol/L、5.08×10-10mmol/L10 gradient concentrations.
Blank control 10% HClO was added immediately after MAO addition4200 μ L of the inactivated cells were inactivated, and the rest of the procedure was the same.
The samples of each example and the positive controls rasagiline, selegiline and clorgoline were tested as shown in table 1. It can be seen that the IC measured for the compounds of the invention50The value is 10 to 2000nM, most of which is 30 to 400nM,the partial compounds have the inhibitory activity on MAO-B superior to positive contrast rasagiline, selegiline and clorgoline, and the internal selectivity of MAO families of the compounds is greatly improved.
TABLE 1
Figure BDA0001217358220000321
Denotes IC50Test value>100μM。

Claims (1)

1. Indane derivatives useful as MAO-B inhibitors, characterized by: the indane derivative is 4-chloro-N- (3-2- (1- (propargyl-1-aminoindan) -4-yloxy) -ethoxyphenyl) -benzamide, and the structural formula is shown as follows:
Figure FDA0002171135280000011
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