CN104109143A - Melatonin (MT1-MT2) receptor stimulant, and preparation method and use thereof - Google Patents

Melatonin (MT1-MT2) receptor stimulant, and preparation method and use thereof Download PDF

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CN104109143A
CN104109143A CN201410163829.3A CN201410163829A CN104109143A CN 104109143 A CN104109143 A CN 104109143A CN 201410163829 A CN201410163829 A CN 201410163829A CN 104109143 A CN104109143 A CN 104109143A
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organic solvent
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CN104109143B (en
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陈友喜
郜飞
贺礼东
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Nanjing Changao Pharmaceutical Science and Technology Co Ltd
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Shanghai Sun Sail Pharmaceutical Science and Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Abstract

The invention discloses a melatonin (MT1-MT2) receptor stimulant. The melatonin (MT1-MT2) receptor stimulant is a compound represented by general formula (I) or its optical isomer. In the general formula (I), n is selected from 1-5; A is selected from CH2, oxygen and NH; D is selected from CH2 and oxygen, a special bond shown in the specification is selected from = (double bond) and - (single bond); B is selected from groups shown in the specification; R is selected from H, C1-C6 saturated linear alkyl groups, C3-C6 saturated branched alkyl groups, C3-C6 naphthenic groups and C3-C6 unsaturated liner or branched alkyl groups; R1 is selected from hydrogen and fluorine; R2 is selected from hydrogen, a hydroxy group, mercapto groups, amino groups, halogens and C1C6 linear or branched alkyl groups; R3 is selected from C1-C6 linear alkyl groups and C3-C6 branched alkyl groups; and the alkyl groups are unsubstituted alkyl groups or alkyl groups substituted by one or three groups independently selected from halogens, OH, NH2 and CN. The invention also discloses a preparation method of the compound, and an application of the compound in the preparation of medicines for treating melatonin MT1-MT2 receptor-related diseases.

Description

One class melatonin (MT1-MT2) receptor stimulant and preparation method thereof and purposes
Technical field
The invention belongs to pharmacology, pharmaceutical chemistry and area of pharmacology, particularly relate to the novel melatonin of a class (MT1-MT2) receptor stimulant, the preparation method of this compounds and the application in the medicine of the diseases such as preparation treatment and the relevant insomnia of melatonin (MT1-MT2) acceptor, anxiety, depression thereof.
Background technology
Insomnia is common clinical disease, and sickness rate is very high.It is reported, the U.S. is in the past in 20 years, and insomnia morbidity is about 30%～35%, and wherein 10%～15% patient reaches severe degree; Britain and Australian investigation result are similarly.China has difficulty falling asleep, dreaming often and waking easily at present, be difficult to after waking up to fall asleep again, early morning the insomnia such as early awakening adult patients approximately 300,000,000.And this situation has the trend of rising.Sleep specialist claims insomnia for " the quietly prevailing disease of expansion ".Therefore, the medicine of exploitation treatment of insomnia patients is significant.
The clinical drug main that is used for the treatment of insomnia will comprise Chinese medicine and chemical drugs both at home and abroad.Chemical drugs mainly contains barbiturates, benzodiazepine receptors agonist class, non-benzodiazepine receptors agonist and melatonin (MT1/MT2) receptor stimulant etc.
Melatonin (MT1/MT2) receptor stimulant is a kind of novel anti-insomnia medicine.Melatonin (Metatonin) such as is present in from lower algae to the mankind at a kind of important hormone in numerous biologies, and its contents level in organism changed with the time of every day.In higher animal, melatonin is by retina, eye lens, and the pinealocyte of gi tract and pineal gland (being arranged in brain) is manufactured.How many pineal glanies can decide according to the received light quantity of our eyeball and intensity the amount of melatonin secretion, the light quantity that in one day, our eyeball is accepted is different with intensity, pineal gland has served as a clock in human body, is controlling the time of reviving every day and sleeping.When nighttime sleep, people knows from experience a large amount of melatonin of secretion, and the secretory volume after early morning declines rapidly.
Melatonin can system adjusting sleep mechanism, optical information (diel rhythm) physiological clock pacemaker in retina is delivered to body---the diencephalon suprachiasmatic nucleus (SCN) in ambient lighting cycle, SCN is by regulation and control pineal gland secretion melatonin.SCN is exactly known " physiological clock " [Exp Gerontol.2003; 38:199 – 206], it regulates the human body periodicity biorhythm of 24 hours, wherein just comprises this cycle of falling asleep-regain consciousness.The secretion low night on daytime high (night is higher than 1～2 times in the daytime) of melatonin, with light the cycle, sleep biorhythm consistent.Because it has calmness, induced hypnotic effect, so melatonin is called as physiological soporific.Melatonin need be by activating melatonin receptors performance biological action.
Melatonin receptors belongs to G protein coupling receptor superfamily member, is extensively present in the cytolemma and nucleus of the other systems such as neural SCN, hippocampus, cerebellar cortex, prefrontal lobe, Basal ganglia, black substance ventral tegmental area and retina, blood vessel, mammary gland, liver, kidney, gi tract and sexual gland.Mankind's melatonin receptors has MT1, MT2 and tri-hypotypes of MT3.Wherein MT1 is highly gathered in the part such as SCN, nervus thalamicus core, regulates sleep, and MT2 relates to joint round the clock, and MT3 effect is not clear.[Richardson?G.The?human?circadian?system?in?normal?and?disordered?sleep.J?Clin?Psychiatry.2005.]
Melatonin secretion reduces relevant with somnopathy.The elderly's melatonin secretion amount only has the 1/l0 of peak period.The diseases such as primary insomnia, diel rhythm imbalance, alzheimer's disease and depression all exist melatonin secretion amount abnormal.Therefore, exploitation melatonin (MT1/MT2) receptor stimulant, to diseases such as Cure for insomnia, anxiety, depressions, has important meaning.Therefore, development of new melatonin (MT1/MT2) receptor stimulant medicine, become the focus of the current anti-insomnia of development of new in the world medicine research and development, many major companies and institutions for academic research are all actively developed correlative study, and obtained immense success, such medicine will be strong rival in Cure for insomnia kind new medicine.[Sleep?Med.2007；8:623–636.]
The MT1/MT2 receptor agonism agent medicine ramelteon (Ramelteon) of being researched and developed by Japanese Takeda Pharmaceutical Company Limited, obtains FDA approval listing in July, 2005, can be used for especially sleep initial delay patient's long-term treatment of insomnia.Result of study shows, uses the untoward reaction such as aftereffect that there will not be excessive use, withdrawal reaction, drug dependence and second day after this medicine.[Drugs?Today42(4):255–63]
The structure of Metatonin and Ramelteon
Ramelteon is that the first is also uniquely a kind ofly can not cause patient to produce drug-dependent prescription class soporific, and therefore it is not classified as control similar drug by united states drug control office.Except ramelteon, other prescription class soporific is all listed in IV class control product, is enough to show the safe of this product, without habituation.
The external MT1/MT2 receptor agonist activity of ramelteon is very high, EC 50<1nM, but due to its transformation period shorter [J Clin Sleep Med3 (5): 495 – 504], in brain, abundance is little, affect giving full play to of its drug action, it is not very strong causing its clinical anti-insomnia effect, is only applicable to treatment slightly and moderate insomniac.
The present invention will provide a class novel MT1/MT2 receptor stimulant, and this excitomotor will overcome the above-mentioned defect of ramelteon, have anti-insomnia activity and security.
Summary of the invention
Primary and foremost purpose of the present invention is to provide a class novel melatonin (MT1/MT2) receptor stimulant or its optical isomer shown in general formula (I), their Preparation method and use.
In a first aspect of the present invention, a class melatonin receptor agonist is provided, it is the compound shown in general formula (I) or its optical isomer:
Wherein:
N is selected from: 1-5;
A is selected from: CH 2, oxygen, or NH;
be selected from: (two key) or-(singly-bound);
D is selected from: CH 2or oxygen;
B is selected from:
Wherein R is selected from: hydrogen, C 1-C 6straight chain saturated alkyl or C 3-C 6saturated branched-chain alkyl or C 3-C 6cycloalkyl or C 3-C 6unsaturated straight or branched alkyl (saturated alkyl is the alkyl that does not contain two keys or triple bond, and unsaturated alkyl is the alkyl that comprises two keys or triple bond); Described alkyl is unsubstituted or is replaced by one to three group that is independently selected from lower group: halogen, OH, NH 2, or CN;
R 1be selected from hydrogen or fluorine;
R 2be selected from hydrogen, hydroxyl, sulfydryl, amino, halogen or C 1-C 6straight or branched alkyl;
R 3be selected from C 1-C 6straight chained alkyl or C 3-C 6branched-chain alkyl; Described alkyl is unsubstituted or is replaced by one to three group that is independently selected from lower group: halogen, OH, NH 2, or CN.
General formula of the present invention (I) contains 1 or 2 chiral carbon atoms, and therefore, shown in formula (I), compound comprises single enantiomer, non-enantiomer mixture, racemic modification and single diastereomer.
In the compound of general formula (I), title and the structural formula of the preferred compound of part are as shown in table 1.
Table 1 part representative compound of the present invention
In a second aspect of the present invention, provide the preparation method of general formula (I) compound.
Compound of the present invention can be prepared by reaction process and description below:
Flow process 1:
At suitable temperature, add organic solvent dissolution formula A-1 compound, formula A-2 compound, coupling reagent, alkali, reaction obtains formula IA compound.
Above-mentioned organic solvent is selected non-protonic solvent, preferably methylene dichloride, DMF (dimethyl formamide), acetonitrile and toluene.Coupling reagent is EDC. hydrochloride (N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), DIC (N, N'-DIC), DCI (4, 5-dicyano imidazole), CDI (N, N'-carbonyl dimidazoles), HOBt (1-hydroxy benzo triazole), HOAT (1-hydroxyl-7-azo benzotriazole), HATU (O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester), TBTU (O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester), HBTU (benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester), HTCU (6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester), alkali is organic bases or mineral alkali, the preferred salt of wormwood of mineral alkali, cesium carbonate, sodium carbonate, the preferred DMAP of organic bases (DMAP), triethylamine, DI ethyl acetate (diisopropylethylamine), the molar ratio of formula A-2 compound and formula A-1 compound is 1.1-2, is preferably 1.1-1.5 equivalent, the molar ratio of coupling reagent and formula A-1 compound is 1.1-2, is preferably 1.1-1.5 equivalent, alkali and formula A-1 compound molar ratio are 1.0-10.0, are preferably 1.5-3 equivalent, temperature of reaction is 0-100 DEG C, is preferably 20-80 DEG C, reaction times is 5-48 hour, is preferably 5-15 hour.
Flow process 2:
L) reduction of formula B-1 compound obtains formula B-2 compound.
Reductive agent is dissolved in organic solvent, slowly adds the organic solvent solution of formula B-1 compound, after reaction, obtain formula B-2 compound.
Above-mentioned organic solvent is selected non-protonic solvent, ethyl acetate, tetrahydrofuran (THF), toluene, DMF; Reductive agent is sodium borohydride-lewis acid system, sodium borohydride-organic acid acid system, lithium aluminum hydride, diisobutyl aluminium hydride, red aluminium, K-selectride, preferably lithium aluminum hydride; Temperature of reaction is 0-60 DEG C, is preferably 20-40 DEG C; Reaction times is 0.5-24 hour, is preferably 0.5-10 hour.
2) formula B-2 compound transforms and obtains formula B-3 compound.
Formula B-2 compound is dissolved in organic solvent, adds alkali, drip methylsulfonyl chloride (Methanesulfonyl chloride), room temperature reaction obtains formula B-3 compound.
Above-mentioned organic solvent is selected non-protonic solvent, ethyl acetate, tetrahydrofuran (THF), toluene, DMF; Alkali is mineral alkali or organic bases, is preferably triethylamine, salt of wormwood, sodium carbonate, potassium tert.-butoxide and cesium carbonate; The molar ratio of alkali and formula B-2 compound is 1.0-20.0, is preferably 2-3 equivalent; Temperature of reaction is 0-60 DEG C, is preferably 20-30 DEG C; Reaction times is 1-48 hour, is preferably 1-4 hour.
3) formula B-3 compound transforms and obtains formula B-4 compound.
Formula B-3 compound is dissolved in organic solvent, adds cyanide salt, reaction obtains formula B-4 compound.
Above-mentioned organic solvent is selected non-protonic solvent, ethyl acetate, tetrahydrofuran (THF), toluene, DMF; The preferred cyaniding sylvite of cyanide salt or cyaniding sodium salt, itself and formula B-3 compound molar ratio are 1.0-20.0, are preferably 1.0-1.5 equivalent; Temperature of reaction is 0-160 DEG C, is preferably 90-110 DEG C; Reaction times is 1-24 hour, is preferably 1-4 hour.
4) formula B-4 compound transforms and obtains formula B-5 compound.
Formula B-4 compound is dissolved in organic solvent, adds alkali and hydrogen peroxide, reaction obtains formula B-5 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferably DMSO (dimethyl sulfoxide (DMSO)); Alkali is mineral alkali or organic bases, is preferably salt of wormwood, sodium carbonate, cesium carbonate, sodium bicarbonate, saleratus, potassium tert.-butoxide or sodium tert-butoxide; Hydrogen peroxide is 30% (mass percent concentration) hydrogen peroxide preferably; The molar ratio of alkali and formula B-4 compound is 1.0-10.0, is preferably 1-2 equivalent; The molar ratio of hydrogen peroxide and formula B-4 compound is 1.0-10.0, is preferably 1-5 equivalent; Temperature of reaction is 0-100 DEG C, is preferably 20-60 DEG C; Reaction times is 1-24 hour, is preferably 1-4 hour.
Flow process 3:
1) formula B-4 compound transforms and obtains formula C-1 compound.
Formula B-4 compound is dissolved in organic solvent, adds alkali, reaction obtains formula C-1 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferred alcohol, methyl alcohol, a kind of or any multiple mixture in water; Alkali is mineral alkali, is preferably potassium hydroxide, sodium hydroxide; The molar ratio of alkali and formula B-4 compound is 1.0-10.0, is preferably 1-3 equivalent; Temperature of reaction is 0-160 DEG C, is preferably 60-100 DEG C; Reaction times is 1-24 hour, is preferably 1-4 hour.
2) formula C-1 compound transforms and obtains formula IC compound.
At suitable temperature, add organic solvent dissolution formula C-1 compound, aminated compounds, coupling reagent, alkali, reaction obtains formula IC compound.
Above-mentioned organic solvent is selected non-protonic solvent, preferably methylene dichloride (methylene dichloride), DMF (dimethyl formamide), acetonitrile and toluene.Aminated compounds is the simple amine of C1-C6, is preferably methylamine, ethamine, propylamine, Isopropylamine, n-Butyl Amine 99, isobutyl ammonia, cyclopropylamine, coupling reagent is EDC. hydrochloric acid (N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride), DCC (dicyclohexylcarbodiimide), DIC (N, N'-DIC), DCI (4, 5-dicyano imidazole), CDI (N, N'-carbonyl dimidazoles), HOBt (1-hydroxy benzo triazole), HOAT (1-hydroxyl-7-azo benzotriazole), HATU (O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester), TBTU (O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester), HBTU (benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester), HTCU (6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester), alkali is organic bases or mineral alkali, the preferred salt of wormwood of mineral alkali, cesium carbonate, sodium carbonate, the preferred DMAP of organic bases (DMAP), triethylamine, DI ethyl acetate (diisopropylethylamine), the molar ratio of aminated compounds and formula C-1 compound is 1.1-2, is preferably 1.1-1.5 equivalent, the molar ratio of coupling reagent and formula C-1 compound is 1.1-2, is preferably 1.1-1.5 equivalent, alkali and formula C-1 compound molar ratio 1.0-10.0, be preferably 1.5-3 equivalent, temperature of reaction is 0-100 DEG C, is preferably 20-80 DEG C, reaction times is 5-48 hour, is preferably 5-15 hour.
Flow process 4:
1) formula C-1 compound transforms and obtains formula D-1 compound.
Formula C-1 compound is dissolved in organic solvent, adds acid, reaction obtains formula D-1 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, is preferably methyl alcohol; Acid is sulfuric acid, hydrochloric acid, phosphoric acid, is preferably sulfuric acid; Acid is 1.0-10.0 with the molar ratio of formula C-1 compound, is preferably 1-2 equivalent; Temperature of reaction is 0-160 DEG C, is preferably 60-100 DEG C; Reaction times is 1-24 hour, is preferably 1-4 hour.
2) formula D-1 compound transforms and obtains formula ID compound.
At suitable temperature, add organic solvent dissolution formula D-1 compound, methylamine, reaction obtains formula ID compound.
Above-mentioned organic solvent is selected non-protonic solvent, preferably tetrahydrofuran (THF) (tetrahydrofuran (THF)), methylene dichloride (methylene dichloride), acetonitrile and toluene.The molar ratio of methylamine and formula D-1 compound is 1.1-2, is preferably 1.1-1.5 equivalent; Temperature of reaction is 0-100 DEG C, is preferably 20-80 DEG C; Reaction times is 5-48 hour, is preferably 5-15 hour.
Flow process 5:
1) formula E-1 compound transforms and obtains formula E-2 compound.
Formula E-1 compound is dissolved in organic solvent, adds TosMIC (to Methyl benzenesulfonyl methyl isonitrile) and alkali, reaction obtains formula E-2 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, is preferably methyl alcohol; Alkali is organic bases or mineral alkali, is preferably potassium tert.-butoxide, sodium tert-butoxide, potassium hydroxide, sodium hydroxide; The molar ratio of alkali and formula E-1 compound is 1.0-10.0, is preferably 2-4 equivalent; Temperature of reaction is-10-160 DEG C, is preferably 60-100 DEG C; Reaction times is 1-48 hour, is preferably 5-24 hour.
2) reduction of formula E-2 compound obtains formula E-3 compound.
Reductive agent is dissolved in organic solvent, slowly adds the organic solvent solution of formula E-2 compound, after reaction, obtain formula E-3 compound.
Above-mentioned organic solvent is selected non-protonic solvent, ethyl acetate, tetrahydrofuran (THF), toluene, DMF; Reductive agent is selected from diisobutyl aluminium hydride (DIBAL-H), red aluminium, K-selectride, preferably diisobutyl aluminium hydride; Temperature of reaction is-100-60 DEG C to be preferably-78-0 DEG C; Reaction times is 0.5-24 hour, is preferably 0.5-10 hour.
3) reduction of formula E-3 compound obtains formula E-4 compound.
Ethyl bromide difluoride is added dropwise in the organic solvent that contains activated zinc powder, obtains formula E-4 compound after adding afterwards formula E-3 compound reaction.
Above-mentioned organic solvent is selected non-protonic solvent, ethyl acetate, tetrahydrofuran (THF), toluene, DMF, preferably tetrahydrofuran (THF); Temperature of reaction is 0-100 DEG C, is preferably 10-60 DEG C; Reaction times is 0.5-24 hour, is preferably 0.5-10 hour.
4) reduction of formula E-4 compound obtains formula E-5 compound.
Formula E-4 compound is dissolved in organic solvent, adds dithiocarbonic anhydride and alkali, react after 0.5-5 hour, add methyl iodide, obtain intermediate.
Above-mentioned organic solvent is selected non-protonic solvent, ethyl acetate, tetrahydrofuran (THF), toluene, DMF, preferably DMF; Temperature of reaction is 0-100 DEG C, is preferably 10-60 DEG C; Reaction times is 0.5-24 hour, is preferably 0.5-2 hour.
Above-mentioned intermediate is dissolved in organic solvent, adds peroxy tert-butyl alcohol and triphenyl phosphorus H-H reaction to obtain formula E-5 compound.
Above-mentioned organic solvent is selected non-protonic solvent, preferably Isosorbide-5-Nitrae-dioxane, ethyl acetate, tetrahydrofuran (THF), toluene, DMF, preferably Isosorbide-5-Nitrae-dioxane; Temperature of reaction is 0-100 DEG C, is preferably 10-60 DEG C; Reaction times is 0.5-24 hour, is preferably 3-7 hour.
5) reduction of formula E-5 compound obtains formula E-6 compound.
Formula E-5 compound is dissolved in organic solvent and water mixed solvent, adds alkali, reaction obtains formula E-6 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferred alcohol, methyl alcohol, a kind of or any multiple mixture in water; Alkali is mineral alkali, is preferably potassium hydroxide, sodium hydroxide; The molar ratio of alkali and formula E-5 compound is 0.01-10.0, is preferably 0.1-3 equivalent; Temperature of reaction is 0-160 DEG C, is preferably 60-100 DEG C; Reaction times is 1-24 hour, is preferably 1-4 hour.
6) formula E-6 compound transforms and obtains formula IE compound.
Operation transforms and obtains formula IC compound with flow process 3 Chinese style C-1 compounds.
Flow process 6:
L) reduction of formula F-1 compound obtains formula F-2 compound.
Reductive agent is dissolved in organic solvent, slowly adds the organic solvent solution of formula F-1 compound, after reaction, obtain formula F-2 compound.
Above-mentioned organic solvent is selected non-protonic solvent, ethyl acetate, tetrahydrofuran (THF), toluene, DMF; Reductive agent is sodium borohydride, sodium borohydride-lewis acid system, sodium borohydride-organic acid acid system, lithium aluminum hydride, diisobutyl aluminium hydride, red aluminium, K-selectride, preferably sodium borohydride; Temperature of reaction is 0-60 DEG C, is preferably 20-40 DEG C; Reaction times is 0.5-24 hour, is preferably 0.5-10 hour.
2) formula F-2 compound transforms and obtains formula F-3 compound.
Formula F-2 compound is dissolved in organic solvent, adds alkali and ethyl bromoacetate, reaction obtains formula F-3 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferably tetrahydrofuran (THF), toluene, DMF, ethanol, methyl alcohol, a kind of or any multiple mixture in water; Alkali is mineral alkali, is preferably sodium hydride; The molar ratio of alkali and formula F-2 compound is 0.1-10.0, is preferably 1-3 equivalent; The molar ratio of ethyl bromoacetate and formula F-2 compound is 1-10.0, is preferably 1-3 equivalent; Temperature of reaction is 0-160 DEG C, is preferably 0-100 DEG C; Reaction times is 1-24 hour, is preferably 1-4 hour.
3) formula F-3 compound transforms and obtains formula F-4 compound.
Operation obtains formula E-6 compound with flow process 5 Chinese style E-5 compound reduction.
4) formula F-4 compound transforms and obtains formula IF compound.
Operation transforms and obtains formula IC compound with flow process 3 Chinese style C-1 compounds.
Flow process 7:
L) formula C-1 compound transforms and obtains formula G-1 compound.
Formula C-1 compound is dissolved in organic solvent, adds brominated reagent, reaction obtains formula G-1 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferably tetrahydrofuran (THF), toluene, DMF, ethanol, methyl alcohol, a kind of or any multiple mixture in water; Brominated reagent is phosphorus tribromide, red phosphorus-bromine; The molar ratio of brominated reagent and formula C-1 compound is 1-50.0, is preferably 1-3 equivalent; Temperature of reaction is-50-160 DEG C, is preferably 0-60 DEG C; Reaction times is 1-72 hour, is preferably 1-4 hour.
2) formula G-1 compound transforms and obtains formula G-2 compound.
Formula G-1 compound is dissolved in organic solvent and water mixed solvent, adds alkali, reaction obtains formula G-2 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferred alcohol, methyl alcohol, a kind of or any multiple mixture in water; Alkali is mineral alkali, is preferably potassium hydroxide, sodium hydroxide; The molar ratio of alkali and formula G-1 compound is 0.01-10.0, is preferably 0.1-3 equivalent; Temperature of reaction is-50-160 DEG C, is preferably 0-100 DEG C; Reaction times is 1-48 hour, is preferably 1-4 hour.
3) formula G-2 compound transforms and obtains formula IG compound.
Operation transforms and obtains formula IC compound with flow process 3 Chinese style C-1 compounds.
Flow process 8:
1) formula IG compound (formula IG compound makes by the method for above-mentioned flow process 7) transforms and obtains formula IH compound.
Formula IG compound is dissolved in organic solvent, adds fluoro reagent, reaction obtains formula IH compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferably methylene dichloride, tetrahydrofuran (THF), a kind of or any multiple mixture in toluene; Fluoro reagent is preferably DAST (diethylin sulfur trifluoride); The molar ratio of fluoro reagent and formula IG compound is 1-50.0, is preferably 1-5 equivalent; Temperature of reaction is-50-100 DEG C, is preferably 20--20 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.Flow process 9:
1) formula G-1 compound (formula G-1 compound makes by the method for above-mentioned flow process 7) transforms and obtains formula I-1 compound.
Formula G-1 compound is dissolved in solvent, adds sulfo-reagent, reaction obtains formula I-1 compound.
Above-mentioned solvent is selected protic or non-protonic solvent, preferably water, DMF (DMF), a kind of or any multiple mixture in DMSO (dimethyl sulfoxide (DMSO)); Sulfo-reagent is preferably Sodium sulfhydrate; The molar ratio of sulfo-reagent and formula G-1 compound is 1-50.0, is preferably 1-5 equivalent; Temperature of reaction is-50-100 DEG C to be preferably-20～20 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.
2) formula I-1 compound transforms and obtains formula II compound.
Operation transforms and obtains formula II compound with flow process 3 Chinese style C-1 compounds.
Flow process 10:
1) formula G-1 compound (formula G-1 compound makes by the method for above-mentioned flow process 7) transforms and obtains formula J-1 compound.
Formula G-1 compound is dissolved in solvent, adds nitrine reagent, reaction obtains formula J-1 compound.
Above-mentioned solvent is selected protic or non-protonic solvent, preferably DMF (DMF), a kind of or any multiple mixture in DMSO (dimethyl sulfoxide (DMSO)); Nitrine reagent is preferably sodiumazide; The molar ratio of nitrine reagent and formula J-1 compound is 1-50.0, is preferably 1-5 equivalent; Temperature of reaction is-50-100 DEG C to be preferably 0～50 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.
2) formula J-1 compound transforms and obtains formula J-2 compound.
Operation transforms and obtains formula J-2 compound with flow process 3 Chinese style C-1 compounds.
3) formula J-2 compound transforms and obtains formula IJ compound.
Formula J-2 compound is dissolved in solvent, and reduction obtains formula IJ compound.
Above-mentioned solvent is selected protic or non-protonic solvent, preferably tetrahydrofuran (THF), methylene dichloride, a kind of or any multiple mixture in toluene; Also original reagent is preferably triphenyl phosphorus/aqueous systems, hydrogen/palladium carbon system; Also the molar ratio of original reagent and formula J-2 compound is 1-50.0, is preferably 1-5 equivalent; Temperature of reaction is-50-100 DEG C to be preferably-30～30 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.Conversion obtains formula IJ compound.
Flow process 11:
1) formula C-1 compound (formula C-1 compound makes by the method for above-mentioned flow process 7) transforms and obtains formula K-1 compound.
Formula C-1 compound is dissolved in organic solvent, adds alkylating reagent, reaction obtains formula K-1 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferably tetrahydrofuran (THF), toluene, normal hexane, a kind of or any multiple mixture in methylene dichloride; Alkylating reagent is preferably methyl iodide, monobromethane, n-propyl bromide, methyl-sulfate; The molar ratio of alkylating reagent and formula G-1 compound is 1-50.0, is preferably 1-5 equivalent; Temperature of reaction is-80-100 DEG C to be preferably-80～20 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.
2) formula K-1 compound transforms and obtains formula IK compound.
Operation transforms and obtains formula IK compound with flow process 3 Chinese style C-1 compounds.
Flow process 12:
1) formula B-1 compound transforms and obtains formula L-1 compound.
Formula L-1 compound is dissolved in organic solvent, adds oxidising agent, reaction obtains formula L-1 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferably tetrahydrofuran (THF), toluene, normal hexane, a kind of or any multiple mixture in methylene dichloride; Oxidising agent is preferably Manganse Dioxide, oxalyl chloride/methyl-sulphoxide/triethylamine system, Dess-Martin oxygenant, PCC (pyridinium chlorochromate), PDC (chlorine dichromic acid pyridine), methyl-sulphoxide-sulphur trioxide complex compound, two oxidation of methylpyridine chromium; The molar ratio of oxidising agent and formula L-1 compound is 1-50.0, is preferably 1-5 equivalent; Temperature of reaction is-80-100 DEG C to be preferably-80～20 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.
2) formula L-1 compound transforms and obtains formula L-2 compound.
Formula L-1 compound is dissolved in organic solvent, adds chiral ligand, cyanating reagent, after triphen oxygen phosphorus reaction for some time, acidifying is adjusted pH=1～2 to continue reaction and is obtained formula L-2 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferably tetrahydrofuran (THF), toluene, normal hexane, a kind of or any multiple mixture in methylene dichloride; Chiral ligand is preferably (S)-bis-(3,5-dimethyl is stupid) (synthetic method is referring to document Journal of Organic Chemistry for (pyrrolidin-2-yl) methyl alcohol, 2007,72 (18): 7066-7069); Cyanating reagent is preferably trimethyl silicane nitrile, potassium cyanide; The molar ratio of chiral ligand and formula L-1 compound is 0.01-50.0, is preferably 0.1 equivalent of 0.01 –; The molar ratio of cyanating reagent and formula L-1 compound is 1-50.0, is preferably 5 equivalents of 1 –; The molar ratio of triphen oxygen phosphorus and formula L-1 compound is 0.01-50.0, is preferably 0.2 equivalent of 0.01 –; Described acidifying be preferably concentrated hydrochloric acid (36%), methanesulfonic, the vitriol oil, phosphoric acid with acid; Temperature of reaction is-80-100 DEG C to be preferably-80～20 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.
3) formula L-2 compound transforms and obtains formula L-3 compound.
Formula L-2 compound is dissolved in organic solvent, adds acid, reaction obtains formula L-3 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, a kind of or its mixture in particular methanol, ethanol; Acid is preferably concentrated hydrochloric acid (36%), methanesulfonic, the vitriol oil, phosphoric acid; Acid with solvent the volume ratio that feeds intake be 0.01 – 1, be preferably 0.2 equivalent of 0.01 –; Temperature of reaction is-80-100 DEG C to be preferably-80～20 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.
4) formula L-3 compound transforms and obtains formula L-4 compound.
Formula L-3 compound is dissolved in organic solvent, adds alkali, reaction obtains formula L-4 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, a kind of or its mixture in particular methanol, ethanol, tetrahydrofuran (THF); Alkali is preferably sodium hydroxide, potassium hydroxide, lithium hydroxide; The molar ratio of alkali and formula L-3 compound is 1 – 50, is preferably 5 equivalents of 1 –; Temperature of reaction is-80-100 DEG C to be preferably-80～20 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.
4) formula L-4 compound transforms and obtains formula IL compound.
Operation transforms and obtains formula IK compound with flow process 3 Chinese style C-1 compounds.
Flow process 13:
1) formula L-1 compound transforms and obtains formula M-1 compound.
Formula L-1 compound is dissolved in organic solvent, adds chiral ligand, cyanating reagent, after triphen oxygen phosphorus reaction for some time, acidifying is adjusted pH=1～2 to continue reaction and is obtained formula L-2 compound.
Above-mentioned organic solvent is selected protic or non-protonic solvent, preferably tetrahydrofuran (THF), toluene, normal hexane, a kind of or any multiple mixture in methylene dichloride; Chiral ligand is preferably (R)-bis-(3,5-dimethyl is stupid) (synthetic method is referring to document Journal of Organic Chemistry for (pyrrolidin-2-yl) methyl alcohol, 2007,72 (18): 7066-7069); Cyanating reagent is preferably trimethyl silicane nitrile, potassium cyanide; The molar ratio of chiral ligand and formula L-1 compound is 0.01-50.0, is preferably 0.1 equivalent of 0.01 –; The molar ratio of cyanating reagent and formula L-1 compound is 1-50.0, is preferably 5 equivalents of 1 –; The molar ratio of triphen oxygen phosphorus and formula L-1 compound is 0.01-50.0, is preferably 0.2 equivalent of 0.01 –; Described acidifying be preferably concentrated hydrochloric acid (36%), methanesulfonic, the vitriol oil, phosphoric acid with acid; Temperature of reaction is-80-100 DEG C to be preferably-80～20 DEG C; Reaction times is 1-72 hour, is preferably 1-5 hour.
2) formula M-1 compound transforms and obtains formula M-2 compound.
Operation transforms and obtains formula L-3 compound with flow process 12 Chinese style L-2 compounds.
3) formula M-2 compound transforms and obtains formula M-3 compound.
Operation transforms and obtains formula L-4 compound with flow process 12 Chinese style L-3 compounds.
4) formula M-3 compound transforms and obtains formula IM compound.
Operation transforms and obtains formula IL compound with flow process 12 Chinese style L-4 compounds.
In a third aspect of the present invention, provide the purposes of general formula (I) compound, i.e. the application of general formula (I) compound in the medicine of preparing diseases such as treating the insomnia relevant to melatonin (MT1-MT2) acceptor, anxiety, depression.
Compound of the present invention can be with together with carrier pharmaceutically, and composition pharmaceutical composition, is used for the treatment of the diseases such as the insomnia relevant to melatonin (MT1-MT2) acceptor, anxiety, depression.
In the present invention, pharmaceutically acceptable carrier refers to the pharmaceutical carrier of pharmaceutical field routine, comprising: thinner, vehicle (as water), weighting agent (as starch), tamanori (as gelatin), disintegrating agent (calcium carbonate), absorption enhancer (as quaternary ammonium compound), tensio-active agent (as cetyl alcohol), lubricant (as talcum powder), correctives etc.
Melatonin of the present invention (MT1-MT2) receptor stimulant can pharmaceutical composition mode use with the significant quantity in treatment, its method of application can be oral, systemic administration (for example, transdermal, snuffing enter or with suppository).
The various formulations of pharmaceutical composition of the present invention can be according to the ordinary method preparation of pharmaceutical field.For example make this melatonin (MT1-MT2) receptor stimulant (activeconstituents) mix with one or more carriers, then be made into required formulation, as tablet, pill, capsule, semisolid, powder, slow release formulation, solution, suspension, ingredients, aerosol etc.
Melatonin (MT1-MT2) receptor agonism dosage in pharmaceutical composition of the present invention (formulation) can change in those skilled in the art's four corner used.Conventionally, (wt%) note, contains melatonin (MT1-MT2) receptor stimulant that accounts for the about 0.1-99.5wt% of total formulation in formulation by weight percentage, and also has one or more suitable drug excipients as equipoise.Preferably, compound exists with the ratio of about 0.5-95wt%.
The actual amount of application (being active ingredient) of melatonin of the present invention (MT1-MT2) receptor stimulant depends on many factors, as usefulness, route of administration and the form of the age of the seriousness of disease to be treated, treatment target and relative health degree, the compound that used, and other factors, specifically can be, approximately per daily dose is 0.01-50mg/kg acceptor body weight; Preferred about 0.1-10mg/kg/day, can use by one or many.
Major advantage of the present invention is: melatonin (MT1-MT2) receptor stimulant shown in general formula of the present invention (I) or its optical isomer are melatonin (MT1-MT2) receptor stimulants of a class recruit structure, they have the active and excellent drug metabolism character of very strong inhibition and good security to melatonin (MT1-MT2) acceptor, are particularly suitable as melatonin (MT1-MT2) receptor stimulant and are used for the treatment of the diseases relevant to melatonin (MT1-MT2) acceptor such as insomnia, anxiety, depression.In addition, the invention also discloses the preparation method of above-mentioned melatonin (MT1-MT2) receptor stimulant.
Embodiment
Below in conjunction with embodiment, in his-and-hers watches 1, the preparation method of each melatonin (MT1-MT2) receptor stimulant is further described in detail.Wherein:
Thin-layer chromatography (TLC) carries out on the thick HF254 silica-gel plate of prefabricated 0.5mm.
The silica gel of column chromatography is H type 10-40 μ, 1brukerAMX-400 type nmr determination for H NMR spectrum, mass spectrum is measured with HP5989A or VG Quattro MS/MS mass spectrograph, and ionization mode has EI (electron ionization ion source), FAB (fast atom bombardment source) and ESI (electrospray ionization source).
Tetrahydrofuran (THF) is first pressed sodium silk, then adds benzophenone and be back to blueness, under nitrogen protection, steams.
Methylene dichloride, adds calcium hydrogen and refluxes, and under nitrogen protection, steams.
Dimethyl formamide (DMF) directly uses after spending the night by new molecular sieve drying of drying.
Triethylamine (TEA) reinforcing body KOH stirred overnight at room temperature.
Other solvent and reagent except specified otherwise by standard method be dried, purifying and processing.In detail purification step can reference: Purification of Laboratory Chemicals, 4th Ed., Armarego, W.L.F.; Perrin, D.D.Butterworth-Heinem ann, 1998.
Compound method and the use range of the developer using in embodiment are as follows:
Ammonium molybdate-sulfuric acid developer: slowly add vitriol oil 20mL in the 100mL aqueous solution of 20g ammonium molybdate, then be diluted with water to 300mL.
Phospho-molybdic acid-ethanolic soln: the ethanolic soln of 3～15% (mass percents) of phospho-molybdic acid.
Potassium permanganate dilute solution: 1g potassium permanganate and 1g sodium bicarbonate are dissolved in configuration in 100mL water and form.
Iodine steam: solid iodine 0.5g and appropriate thick silica gel mixed configuration.
In embodiment, other prepare the required raw material of each compound, if no special instructions, are all known in the art or can directly buy acquisition.
Below in conjunction with specific embodiment, further set forth the present invention.Should be appreciated that these embodiment, only for the present invention is described, limit the scope of the invention and be not used in.The experimental technique of unreceipted actual conditions in the following example, conventionally according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.
Embodiment 12, the preparation of the fluoro-N-of 2-bis-(2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) ethyl) propionic acid amide (formula 1 compound)
Methylene dichloride dissolution type 1-1 compound (101.64mg, 0.5mmol that 4mL is dry; Its synthetic method is shown in US6034239A1,2000) and, ice bath is chilled to 0 DEG C, add successively EDC-hydrochloride (94.44mg, 0.55mmol), DMAP (67.2mg, 0.55mmol) and 2,2-difluoro propionic acid (57.78mg, 0.525mmol), room temperature reaction 1-2 hour, concentrated, column chromatography for separation, obtain 24mg white solid (being formula 1 compound), productive rate is 23%.
Formula 1 compound: 1h NMR (400MHz, CDCl 3) δ 6.95 (d, J=8.0Hz, 1H), 6.62 (d, J=8.1Hz, 1H), 6.32 (s, 1H), 4.56 (ddt, J=18.3,16.7,5.3Hz, 2H), 3.48 – 3.34 (m, 2H), 3.21 (d, J=9.0Hz, 2H), 3.16 – 3.03 (m, 1H), 3.00 – 2.86 (m, 1H), 2.83 (dd, J=33.0,7.3Hz, 2H), 2.30 (dd, J=12.8,6.4Hz, 1H), 2.05 (d, J=5.2Hz, 1H), 1.87 – 1.71 (m, 5H).
The preparation of embodiment 23-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 2 compounds)
Synthetic (the formula 2-2 compound) of step 1.2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) ethanol
Under Ar protection, lithium aluminum hydride (134mg, 3.54mmol) is dissolved in to 10mL tetrahydrofuran (THF), ice bath is chilled to 0 DEG C, slowly adds formula 2-1 compound (290mg, 1.18mmol; Its synthetic method is shown in WO20080106179) tetrahydrofuran solution 5mL, room temperature reaction 1-2h, thin-layer chromatography reacts completely, add the dilution of 5mL tetrahydrofuran (THF), in ice bath, add successively water 0.2mL, sodium hydroxide (15%, mass percent concentration) aqueous solution 0.2mL, stir 10min, add again 0.6mL water, stirring at room temperature 15min.Anhydrous sodium sulfate drying, concentrated, obtain brown jelly 0.24g (being formula 2-2 compound), yield 100%.
Formula 2-2 compound: 1h NMR (400MHz, CDCl 3) δ 6.93 (t, J=15.9Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 4.66 – 4.42 (m, 2H), 3.90 – 3.65 (m, 2H), 3.26 (dt, J=15.0, 9.7Hz, 2H), 3.19 – 3.05 (m, 1H), 2.99 – 2.82 (m, 1H), 2.83 – 2.67 (m, 1H), 2.27 (dtd, J=12.6, 8.3, 6.4Hz, 1H), 2.11 (dtd, J=13.5, 7.5, 4.1Hz, 1H), 1.92 – 1.74 (m, 1H), 1.68 (dddd, J=13.4, 10.1, 6.8, 5.4Hz, 1H). step 2.2-(2, 6, 7, 8-tetrahydrochysene-1H-indeno [5, 4-b] furans-8-yl) synthetic (the formula 2-3 compound) of ethyl methane sulfonate ester (YF-259-31)
Under Ar protection; by formula 2-2 compound (155mg; 0.76mmol) be dissolved in dry tetrahydrofuran (10mL), ice bath is chilled to 0 DEG C, adds triethylamine (123mg; 1.22mmol; 1.6eq), drip methylsulfonyl chloride (105mg, 0.91mmol; 1.2eq); drip complete room temperature reaction 1h, thin-layer chromatography reacts completely, and adds sodium bicarbonate aqueous solution cancellation reaction; ethyl acetate extraction; the washing of organic phase saturated common salt, anhydrous sodium sulfate drying, concentrated; obtain jelly 180mg (being formula 2-3 compound), productive rate is 72%.
Formula 2-3 compound: LC-MS:283.20[M+H] +, 284.20[M+2H] +, 305.20[M+Na] +.
Synthetic (the formula 2-4 compound) of step 3.3-(2,6,7,8-tetrahydrochysene-1H-indenes [5,4-b] furans-8-yl) propionitrile
50mL N, dinethylformamide dissolution type 2-3 compound crude product (8g, 28mmol, 1eq.), add sodium cyanide (4.9g, 100mmol, 5eq.), 85 DEG C of reactions are spent the night, and it is complete that thin-layer chromatography (sherwood oil: ethyl acetate=2:1) detects primitive reaction, pours in trash ice, ethyl acetate extraction, washing, saturated sodium-chloride are washed organic phase, and anhydrous sodium sulfate drying is concentrated, obtain crude product, column chromatography for separation, obtains the colourless jelly of 5.1g (being formula 2-4 compound), and productive rate is 83%.
Formula 2-4 compound: 1h NMR (400MHz, CDCl 3) δ 6.97 (d, J=8.0Hz, 1H), 6.64 (d, J=8.0Hz, 1H), 4.74 – 4.37 (m, 2H), 3.30 (ddd, J=16.3,8.6,3.8Hz, 1H), 3.25 – 3.05 (m, 2H), 2.95 – 2.73 (m, 2H), 2.48 – 2.36 (m, 2H), 2.36 – 2.24 (m, 1H), 2.24 – 2.11 (m, 1H), 1.86 – 1.71 (m, 2H).
Synthesizing of step 4.3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 2 compounds)
By formula 2-4 compound (860mg, 4.03mmol) be dissolved in DMSO (10mL), slowly add salt of wormwood (1.11mg, 8.06mmol), ice bath is chilled to 0 DEG C, drip hydrogen peroxide (30%) (2mL), stirring at room temperature 2 hours, thin-layer chromatography detection reaction is complete, the cancellation that adds water reaction, dichloromethane extraction 3 times, saturated common salt washing 1 time, dried over sodium sulfate, 200～300 order silica gel column chromatographies obtain white solid 887mg (being formula 2 compounds), yield 95%.
Formula 2 compounds: 1h NMR (400MHz, CDCl 3) δ 6.94 (d, J=7.9Hz, 1H), 6.62 (d, J=7.8Hz, 1H), 5.36 (s, 2H), 4.65 – 4.43 (m, 2H), 3.23 (ddd, J=41.2,15.7,7.6Hz, 3H), 2.94 – 2.69 (m, 2H), 2.33 – 2.14 (m, 4H), 1.83 – 1.71 (m, 2H); LC-MS:232.10[M+H] +.
The preparation of embodiment 3.N-methyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 3 compounds)
Step 1-3 is with embodiment 2
Synthesizing of step 4.3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid (formula 3-1 compound)
10mL ethanol and water mixed solvent (volume ratio is 1:1) dissolution type 2-4 compound (100mg, 0.47mmol, 1eq.), 80 DEG C of reactions are spent the night, it is complete that thin-layer chromatography detects primitive reaction, pour in trash ice dichloromethane extraction, saturated common salt water washing organic phase into, anhydrous sodium sulfate drying, concentrated, obtain yellow colloidal crude 201mg (being formula 3-1 compound), productive rate is 100%.
Formula 3-1 compound: LC-MS:232.15[M+H] +.
Synthesizing of step 5.3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) methyl propionate (formula 3-2 compound)
By formula 3-1 compound (860mg, 3.64mmol) be dissolved in methyl alcohol (10mL), drip 3 to 4 vitriol oils, reaction solution is warmed up to 70 DEG C, and back flow reaction is spent the night, and thin-layer chromatography detection reaction is complete, reaction solution is spin-dried for, column chromatography, obtains 862mg colorless oil (being formula 3-2 compound), and productive rate is 96%.
Formula 3-2 compound: LC-MS:247.10[M+H] +.
Synthesizing of step 6.N-methyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 3 compounds)
Formula 3-2 compound (50mg, 0.20mmol, 1eq) is dissolved in tetrahydrofuran (THF), adds 2mL methylamine alcohol solution, room temperature reaction.React after 9 hours, thin-layer chromatography detects unreacted, adds 1mL methylamine alcohol solution, continues reaction 2 days, and thin-layer chromatography detects, and reacts complete, is spin-dried for, and column chromatography obtains 35mg faint yellow solid (being formula 3 compounds), and productive rate is 70%.
Formula 3 compounds: 1h NMR (400MHz, CDCl 3) δ 6.94 (d, J=7.8Hz, 1H), 6.61 (d, J=7.9Hz, 1H), 5.38 (s, 1H), 4.75 – 4.43 (m, 2H), 3.45 – 3.20 (m, 3H), 3.14 (ddd, J=22.6,17.8,15.5Hz, 2H), 2.96 – 2.69 (m, 3H), 2.26 – 2.08 (m, 4H), 1.89 – 1.70 (m, 2H); LC-MS:246.10[M+H] +.
The preparation of embodiment 4.N-ethyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 4 compounds)
Step 1-3 is with embodiment 2
Step 4 is with embodiment 3
Synthesizing of step 5.N-ethyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 4 compounds)
By formula 3-1 compound (143mg, 0.62mmol) be dissolved in anhydrous methylene chloride (10mL), add DMAP (112mg, 0.92mmol), ethamine (42mg, 0.92mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (176mg, 0.92mmol), stirring at room temperature 2 hours, add water, dichloromethane extraction 3 times, saturated common salt washing 1 time, dried over sodium sulfate, 200～300 order silica gel column chromatographies obtain faint yellow solid 136mg (being formula 4 compounds), yield 85%.
Formula 4 compounds: 1h NMR (400MHz, CDCl 3) δ 7.22 (s, 1H), 6.89 (d, J=8.0Hz, 1H), 6.56 (d, J=8.0Hz, 1H), 5.44 (s, 2H), 4.62 – 4.38 (m, 2H), 3.33 – 3.01 (m, 5H), 2.75 (dtd, J=21.9,15.4,6.8Hz, 2H), 2.26 – 2.04 (m, 2H), 1.71 (dd, J=7.2,5.6Hz, 2H), 1.08 (t, J=7.3Hz, 3H); LC-MS:262.20[M+H] +.
The preparation of embodiment 5.N-cyclopropyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 5 compounds 5)
Step 1-3 is with embodiment 2
Step 4 is with embodiment 3
Synthesizing of step 5.N-cyclopropyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 5 compounds)
By formula 3-1 compound (143mg, 0.62mmol) be dissolved in anhydrous methylene chloride (10mL), add DMAP (112mg, 0.92mmol), cyclopropylamine (53mg, 0.92mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (176mg, 0.92mmol), stirring at room temperature 2 hours, add water, dichloromethane extraction 3 times, saturated common salt washing 1 time, dried over sodium sulfate, 200～300 order silica gel column chromatographies obtain faint yellow solid 142mg (being formula 5 compounds), yield 85%.
Formula 5 compounds: 1h NMR (400MHz, CDCl 3) δ 6.89 (d, J=7.9Hz, 1H), 6.56 (d, J=8.0Hz, 1H), 5.58 (s, 1H), 4.66 – 4.32 (m, 2H), 3.15 (ddd, J=16.1,13.7,7.9Hz, 4H), 2.89 – 2.36 (m, 2H), 2.32 – 1.92 (m, 2H), 1.86 – 1.58 (m, 3H), 1.22 (t, J=5.1Hz, 1H), 0.85 – 0.61 (m, 2H), 0.59 – 0.31 (m, 2H); LC-MS:272.20[M+H] +.
The preparation of embodiment 6.N-butyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 6 compounds)
Step 1-3 is with embodiment 2
Step 4 is with embodiment 3
Synthesizing of step 5.N-butyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 6 compounds)
By formula 3-1 compound (143mg, 0.62mmol) be dissolved in anhydrous methylene chloride (10mL), add DMAP (112mg, 0.92mmol), butylamine (67mg, 0.92mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (176mg, 0.92mmol), stirring at room temperature 2 hours, add water, dichloromethane extraction 3 times, saturated common salt washing 1 time, dried over sodium sulfate, 200～300 order silica gel column chromatographies obtain faint yellow solid 159mg (being formula 5 compounds), yield 90%.
Formula 6 compounds: LC-MS:278.2[M+H] +.
The preparation of embodiment 7.3-(7,8-dihydrobenzo [1,2-b:4,3-b'] furans-1-yl)-N-methyl propanamide (formula 7 compounds)
Synthesizing of step 1.1-(4-(2-bromine oxethyl)-2 iodophenyls) ethyl ketone (formula 7-2 compound)
By formula 7-1 compound (44.2g, 0.135mol, 1eq; Its synthetic method is referring to Organic Letters, 2003,5,4827) and Acetyl Chloride 98Min. (11.67g, 0.148mol, 1.1eq) be dissolved in dry methylene dichloride, ice bath to 0 DEG C adds AlCl in batches 3(19.83g, 0.148mol, 1.1eq), after adding, recover room temperature, stirring reaction 3h, thin-layer chromatography detection reaction is complete, ice bath, and cancellation adds water, with 1N sodium hydroxide solution tune, pH clarifies to solution, separatory, water dichloromethane extraction, merge organic phase, anhydrous sodium sulfate drying, filters, be spin-dried for, column chromatography (sherwood oil: ethyl acetate: methylene dichloride=15:1:0.5) obtains 48g faint yellow solid (being formula 7-2 compound), yield 98%.Formula 7-2 compound: LC-MS:267.89[M+H] +.
Synthesizing of step 2.4-(2-bromine oxethyl)-2-iodophenyl acetic ester (formula 7-3 compound)
Formula 7-2 compound (3.4g, 9.2mmol, 1eq) is dissolved in methylene dichloride, adds tosic acid one water (175mg, 0.9mmol, 0.1eq), ice bath.By m-CPBA (4.77g, 27.6mmol, 3eq) be dissolved in methylene dichloride, add in above-mentioned reaction solution, after adding, 0 DEG C of reaction 0.5h, be raised to room temperature and react and spend the night again, thin-layer chromatography detects, and reacts complete, add aqueous sodium persulfate solution cancellation, add aqueous sodium carbonate to solution clarification, separatory, water dichloromethane extraction, merge organic phase, after saturated nacl aqueous solution washing, anhydrous sodium sulfate drying, is spin-dried for, column chromatography obtains 3.422g white solid (formula 7-3 compound), yield 51%.Formula 7-3 compound: LC-MS:384.90[M+H] +.
Synthesizing of step 3.4-(2-bromine oxethyl)-2-iodophenol (formula 7-4 compound)
Sodium methylate is dissolved in methyl alcohol, adjusts pH to 11, ice bath, by formula 7-3 compound (3.422g, 8.89mmol, 1eq) be dissolved in methyl alcohol (30mL) solution of sodium methylate, recover room temperature, stirring reaction 15min, thin-layer chromatography detects, and reacts complete.Adjust solution to neutral with acidic resins, filter, be spin-dried for, by ethyl acetate and water dissolution, separatory, water is extracted with ethyl acetate, and merges organic phase, after saturated common salt water washing, anhydrous sodium sulfate drying, filters and is spin-dried for to obtain 3g yellow oil (formula 7-4 compound), yield 98%.
Formula 7-4 compound: 1h NMR (400MHz, CDCl 3) δ 7.22 (d, J=2.8Hz, 1H), 6.91 (d, J=8.9Hz, 1H), 6.86 (dd, J=8.9,2.8Hz, 1H), 4.21 (t, J=6.2Hz, 2H), 3.60 (t, J=6.2Hz, 2H).
Synthesizing of step 4. (E)-ethyl-4-(4-(2-bromine oxethyl)-2-iodine phenoxy group)-but-2-ene acetoacetic ester (formula 7-5 compound)
Formula 7-4 compound (3.0g, 8.7mmol, 1eq) is dissolved in acetonitrile, adds bromo ethyl crotonate (1.86g, 9.6mmol, 1.1eq) and salt of wormwood (2.42g, 17.5mmol, 2eq), be warmed up to 85 DEG C after adding, reaction is spent the night.Thin-layer chromatography detects, after completion of the reaction, filtration is spin-dried for, after ethyl acetate and water dissolution dilution, separatory, water is extracted with ethyl acetate, and merges organic phase, after saturated common salt water washing, anhydrous sodium sulfate drying, filter, be spin-dried for to obtain 3.94g brown oil (formula 7-5 compound), yield 98%.
Formula 7-5 compound: 1h NMR (400MHz, CDCl 3) δ 7.38 (d, J=2.9Hz, 1H), 7.06 (dt, J=15.7,3.8Hz, 1H), 6.87 (dd, J=8.9,2.9Hz, 1H), 6.71 (d, J=9.0Hz, 1H), 6.33 (dt, J=15.7,2.1Hz, 1H), 4.68 (dd, J=3.8,2.2Hz, 2H), 4.29 – 4.18 (m, 4H), 3.60 (t, J=6.2Hz, 2H), 1.31 (t, J=7.1Hz, 3H).
Synthesizing of step 5. (E)-ethyl-4-(4-(2-iodine oxyethyl group)-2-iodine phenoxy group)-but-2-ene acetoacetic ester (formula 7-6 compound)
Formula 7-5 compound (3.944g, 8.67mmol, 1eq) is dissolved in acetone, adds potassiumiodide (2.877g, 17.33mmol, 2eq), stirring at room temperature 2 days.Thin-layer chromatography detection reaction is complete, is spin-dried for, and adds ethyl acetate and water dilution, separatory, water is extracted with ethyl acetate, and merges organic phase, after saturated common salt water washing, anhydrous sodium sulfate drying, filter, be spin-dried for column chromatography (sherwood oil: ethyl acetate=15:1), obtain 3.113g yellow oil (formula 7-6 compound), yield 72%.Formula 7-6 compound: LC-MS:502.90[M+H] +.
Step 6.2-ethyl (7,8-dihydrobenzo (1,2-b:4,3-b'] furans-1-yl) ethyl acetate (formula 7-7 compound) synthetic
Formula 7-6 compound (3.0g, 5.97mmol, 1eq) is dissolved in DME, add triphenylphosphine (0.157g, 0.597mmol, 0.1eq), palladium (0.134g, 0.597mmol, 0.1eq), norbornylene (5.626g, 59.7mmol, 10eq), cesium carbonate (5.840g, 17.9mmol, 3eq), add and be warmed up to 85 DEG C, reaction is spent the night.Thin-layer chromatography detects, and reacts complete, after filtration, is spin-dried for column chromatography and obtains 402mg yellow oil (being formula 7-7 compound), yield 28%.
Formula 7-7 compound: 1h NMR (400MHz, CDCl 3) δ 7.58 (s, 1H), 7.21 (d, J=8.8Hz, 1H), 6.77 (d, J=8.7Hz, 1H), 4.65 (t, J=8.7Hz, 2H), 4.19 (q, J=7.1Hz, 2H), 3.68 (s, 2H), 3.43 (t, J=8.8Hz, 2H), 1.31 – 1.22 (m, 3H).
Synthesizing of step 7.2-(7,8-dihydrobenzo imidazo [1,2-b:4,3-b'], two furans-1-yl) ethanol (formula 7-8 compound)
Lithium aluminum hydride (62mg, 1.6mmol, 1eq) is added in dry tetrahydrofuran (THF), and ice bath is cooling, is added dropwise to the tetrahydrofuran solution of formula 7-7 compound (402mg, 1.6mmol, 1eq), adds, and recovers room temperature, stirs 15min.Thin-layer chromatography detection reaction is complete, and ice bath slowly adds 0.06mL water, add 0.06mL15% sodium hydroxide solution, add 0.18mL water, stirring at room temperature 15 minutes, adds appropriate anhydrous magnesium sulfate, 15min reduces by half, remove by filter salt, be spin-dried for filtrate, obtain 256mg white solid, for formula 7-8 compound, yield 77%.Formula 7-8 compound: LC-MS:227.1[M+H] +
Synthesizing of step 8.2-(7,8-dihydrobenzo [1,2-b:4,3-b'], two furans-1-yl) ethyl methane sulfonate ester (formula 7-9 compound)
Formula 7-8 compound (256mg, 1.25mmol, 1eq) is dissolved in methylene dichloride, and ice bath, drips triethylamine (634mg, 6.27mmol, 5eq), ice bath, drips methane sulfonyl chloride (431mg, 3.76mmol, 3eq), add recovery room temperature, stirring reaction 1 hour.Thin-layer chromatography detects, and reacts complete, the cancellation that adds water, and dichloromethane extraction, merges organic phase, and saturated common salt water washing, after anhydrous sodium sulfate drying, is filtered, and is spin-dried for to obtain 410mg yellow oil (crude product), for formula 7-9 compound, directly drops into next step.
Synthesizing of step 9.3-(7,8-dihydrobenzo imidazo [1,2-b:4,3-b'], two furans-1-yl) propionitrile (formula 7-10 compound)
Formula 7-9 compound (410mg, 1.25mmol, 1eq) is dissolved in DMF, adds sodium cyanide (307mg, 6.27mmol, 5eq), be warmed up to 85 DEG C, reaction is spent the night.Thin-layer chromatography detects, react complete, be spin-dried for, add water and methylene dichloride dissolved dilution, separatory, water dichloromethane extraction, merges organic phase, saturated common salt water washing, after anhydrous sodium sulfate drying, filter, be spin-dried for column chromatography (sherwood oil: ethyl acetate=3:1) and obtain 91mg faint yellow solid (formula 6-10 compound), two step yields 36%.Formula 7-10 compound: LC-MS:226.1[M+H] +
Synthesizing of step 10.3-(7,8-dihydrobenzo [1,2-b:4,3-b''s] furans-1-yl) propionic acid (formula 7-11 compound)
Formula 7-10 compound (51mg, 0.24mmol, 1eq) is dissolved in to 2mL ethanol and 2mL water, adds 2mL sodium hydroxide (30%) solution, be warmed up to 80 DEG C, reaction is spent the night.Thin-layer chromatography detects, and reacts complete, chooses ethanol, adds after a small amount of water dilution, use 1M hydrochloric acid, adjust pH to 1-2, ethyl acetate extraction, merges organic phase, saturated common salt water washing, after anhydrous sodium sulfate drying, filters and is spin-dried for to obtain 60mg faint yellow solid, is formula 7-11 compound.
Synthesizing of step 11.3-(7,8-dihydrobenzo [1,2-b:4,3-b'] furans-1-yl)-N-methyl propanamide (formula 7 compounds)
By formula 7-11 compound (60mg, 0.24mmol, 1eq) be dissolved in dry methylene dichloride, add HATU (136.4mg, 0.36mmol, 1.5eq), ethamine (0.24mL, 0.48mmol, 2eq), salt of wormwood (50mg, 0.36mmol, 1.5eq), after adding, room temperature reaction spends the night. and thin-layer chromatography detects, react complete, cancellation adds water, dichloromethane extraction, merge organic phase, saturated common salt water washing, after anhydrous sodium sulfate drying, filter, be spin-dried for, column chromatography (sherwood oil: ethyl acetate=2:1) obtains 54mg white solid (being formula 7 compounds), two step yields 87%.Formula 7 compounds: LC-MS:260.1[M+H] +
1H?NMR(400MHz,CDCl 3)δ7.39(s,1H),7.22–7.15(d,J＝8.7Hz,1H),6.76(d,J＝8.7Hz,1H),5.37(s,1H),4.65(t,J＝8.8Hz,2H),3.47(t,J＝8.7Hz,2H),3.33–3.23(m,2H),3.02(dd,J＝11.0,4.1Hz,2H),2.55–2.41(m,2H),1.09(t,J＝7.3Hz,3H).
The preparation of embodiment 8.3-(7,8-dihydrobenzo [1,2-b:4,3-b'] furans-1-yl)-N-methyl propanamide (formula 8 compounds)
Step 1-10 is with embodiment 7
Synthesizing of step 11.3-(7,8-dihydrobenzo [1,2-b:4,3-b'] furans-1-yl)-N-methyl propanamide (formula 8 compounds)
By formula 7-11 compound (60mg, 0.24mmol, 1eq) be dissolved in dry methylene dichloride, add HATU (136.4mg, 0.36mmol, 1.5eq), methylamine (tetrahydrofuran solution of 2M) (0.24mL, 0.48mmol, 2eq), salt of wormwood (50mg, 0.36mmol, 1.5eq), after adding, room temperature reaction spends the night. and thin-layer chromatography detects, react complete, cancellation adds water, dichloromethane extraction, merge organic phase, saturated common salt water washing, after anhydrous sodium sulfate drying, filter, be spin-dried for, column chromatography (sherwood oil: ethyl acetate=2:1) obtains 30mg white solid (being formula 8 compounds), yield 50%.Formula 8 compounds: LC-MS:246.1[M+H] +
The preparation of embodiment 9.33-(7,8-dihydrobenzo [1,2-b:4,3-b'] furans-1-yl)-N-cyclopropyl base propionic acid amide (formula 9 compounds)
Step 1-10 is with embodiment 7
Synthesizing of step 11.3-(7,8-dihydrobenzo [1,2-b:4,3-b'] furans-1-yl)-N-methyl propanamide (formula 9 compounds)
By formula 7-11 compound (60mg, 0.24mmol, 1eq) be dissolved in dry methylene dichloride, add HATU (136.4mg, 0.36mmol, 1.5eq), cyclopropylamine (0.24mL, 0.48mmol, 2eq), salt of wormwood (50mg, 0.36mmol, 1.5eq), after adding, room temperature reaction spends the night. and thin-layer chromatography detects, react complete, cancellation adds water, dichloromethane extraction, merge organic phase, saturated common salt water washing, after anhydrous sodium sulfate drying, filter, be spin-dried for, column chromatography (sherwood oil: ethyl acetate=2:1) obtains 52mg white solid (being formula 9 compounds), yield 80%.Formula 9 compounds: LC-MS:271.1[M+H] +
The preparation of embodiment 10.3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) propionic acid amide (formula 10 compounds)
Step 1.4-is iodo-2,3-dihydro melatonin (formula 10-2 compound) synthetic
Formula 10-1 compound (17.8g, 0.13mol, its synthetic method is referring to WO2009023844) be dissolved in 10% hydrochloric acid (120ml), be cooled to 0 DEG C, Sodium Nitrite (13.65g, 0.19mol) aqueous solution is slowly added dropwise to, add, stir 10 minutes, slowly add urea (6.3g, 0.11mol), stir 10 minutes, under ice bath, slowly drip potassiumiodide (43.78g, the solution (80mL) of water 0.26mol) and methylene dichloride 1:1, add, stirring at room temperature 4 hours, add water and add methylene chloride, organic layer saturated common salt water washing, dried over sodium sulfate, be spin-dried for, column chromatography obtains brown solid (being formula 10-2 compound) (17g, 58%).Formula 7-2 compound: LC-MS:269.0[M+H] +.
Step 2.1-(4-iodo-2,3-dihydro melatonin-5-yl) ethyl ketone (formula 10-3 compound) synthetic
Formula 10-2 compound (17g, 0.069mol) is dissolved in methylene dichloride (100ml), adds Acetyl Chloride 98Min. (5.4ml, 0.0759mmol), under ice bath, add aluminum chloride (10.132mg, 0.076mmol), insulation reaction 3h, thin-layer chromatography detects.The cancellation that adds water, with dichloromethane extraction, is spin-dried for, and column chromatography, obtains yellow solid, i.e. formula 10-3 compound (5.91g, 24%).
Formula 10-3 compound: 1h NMR (400MHz, CDCl 3) δ 7.50 (d, J=8.3Hz, 1H), 6.73 (d, J=8.3Hz, 1H), 4.66 (t, J=8.8Hz, 2H), 3.24 (t, J=8.8Hz, 2H), 2.59 (s, 3H).
Step 3.4-is iodo-2,3-dihydro melatonin-5-yl acetate (formula 10-4 compound) synthetic
By formula 10-3 compound (5.91g, 20.5mmol), tosic acid one water (390mg, 2.05mmol) be dissolved in methylene dichloride (40ml), drip metachloroperbenzoic acid (10.62g, methylene dichloride (60ml) solution 61.5mmol), stirring at room temperature 20h, thin-layer chromatography detects.Add the S-WAT of 1N to stir 20min, add the sodium carbonate of 2N to stir 10min, layering extraction, is spin-dried for, and column chromatography obtains faint yellow solid, i.e. formula 7-4 compound (1.8g, 30%).Formula 10-4 compound: LC-MS:327.0[M+H] +.
Step 4.4-is iodo-2,3-dihydro melatonin-5-alcohol (formula 10-5 compound) synthetic
Formula 10-5 compound (1.8g, 5.9mmol) is dissolved in the methanol solution of sodium methylate of PH=11, room temperature reaction 0.5h, thin-layer chromatography detects.Add acidic resins to be adjusted to neutrality, suction filtration, washing, is spin-dried for, and column chromatography, obtains faint yellow solid 1.586g (being formula 10-6 compound), and crude product directly drops into next step.
Step 5, (Z)-ethyl 4-((4-iodo-2,3-dihydro melatonin-5-yl) oxo) but-2-ene acid esters (formula 10-6 compound) synthetic
Formula 10-5 compound (1.586g, 6.05mmol) is dissolved in acetonitrile (30mL), adds bromo ethyl crotonate (1.60g, 6.66mmol) and salt of wormwood (1.67g, 12.1mmol), add and be warmed up to 85 DEG C, reaction is spent the night.After thin-layer chromatography detection reaction, be spin-dried for, column chromatography, obtains white crystal 1.164g (being formula 10-6 compound), two step yields 53%.Formula 10-6 compound: LC-MS:374.90[M+H] +.
Synthesizing of step 6, ethyl 2-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) acetic ester (formula 10-7 compound)
By formula 10-6 compound (1.164g, 3.11mmol) be dissolved in toluene, 115 DEG C of backflows, add Diisopropyl azodicarboxylate AIBN (11mg, 0.062mmol), after adding, drip slowly Tributyltin hydride (0.996g, toluene solution 3.42mmol), add reaction 3 hours, after thin-layer chromatography detection reaction, be spin-dried for, residue is with after methylene dichloride and KF (60%) solution-treated, under room temperature, stir, by after reacting liquid filtering, separatory, water dichloromethane extraction, merge organic phase, with after saturated sodium-chloride washing, after anhydrous sodium sulfate drying, filter, be spin-dried for, column chromatography, obtain faint yellow solid, be formula 10-7 compound (580mg, 75%).
Formula 10-7 compound: 1h NMR (400MHz, CDCl 3) δ 6.63 – 6.45 (m, 2H), 4.71 (t, J=9.0Hz, 1H), 4.65 – 4.45 (m, 2H), 4.28 (dd, J=9.2,5.8Hz, 1H), 4.17 (q, J=7.1Hz, 2H), 3.93 – 3.71 (m, 1H), 3.23 – 2.99 (m, 2H), 2.79 (dd, J=16.5,4.1Hz, 1H), 2.54 (dd, J=16.5,10.4Hz, 1H), 1.27 (t, J=7.1Hz, 3H).
Synthesizing of step 7, (1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) methyl alcohol (formula 10-8 compound)
By lithium aluminum hydride (88.6mg, 2.336mmol) add in dry tetrahydrofuran (THF), ice bath is cooling, dropping formula 10-7 compound (580mg, 2.336mmol) tetrahydrofuran solution, after dropwising, stir 15 minutes, thin-layer chromatography detect after after completion of the reaction, with appropriate ethyl acetate dilution, be cooled to 0 DEG C, slowly add 0.09mL water, add 0.09mL sodium hydroxide (15%) solution, add again 3 × 0.09mL water, be warmed up to room temperature, stir 15 minutes, add anhydrous sodium sulphate, stir after 15 minutes, filter, be spin-dried for to obtain yellow oil 501mg, it is formula 10-8 compound, crude product directly drops into next step.
Synthesizing of step 8, (1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) methylmethanesulfonate ester (formula 10-9 compound)
Formula 10-8 compound (501mg, 2..336mmol) is dissolved in methylene dichloride, after ice bath, add triethylamine (1.182g, 11.68mmol), ice bath, drips methylsulfonyl chloride (803mg, 7.008mmol), after adding, room temperature reaction one hour, after thin-layer chromatography detection reaction, ice bath, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, with after saturated sodium-chloride washing, anhydrous sodium sulfate drying, filtration is spin-dried for and obtains yellow oil 875mg, be formula 10-9 compound, crude product directly drops into next step.
Synthesizing of step 9,2-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) acetyl nitrile (formula 10-10 compound)
Formula 10-9 compound (875mg, 2.336mmol) is dissolved in DMF, add after NaCN (350mg, 7.008mmol), be warmed up to 85 DEG C, reaction is spent the night, and after thin-layer chromatography detection reaction, adds water and methylene dichloride dilution dissolving, separatory, water dichloromethane extraction, merges organic phase, saturated nacl aqueous solution washing, after anhydrous sodium sulfate drying, filters, be spin-dried for to obtain faint yellow oily matter 263mg, i.e. formula 10-10 compound, three step yields 52%.
Synthesizing of step 10,3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) propionic acid amide (formula 10 compounds)
Formula 10-10 compound (30mg, 0.15mmol) is dissolved in 3mL DMSO, adds salt of wormwood (206mg, 1.5mmol), drip hydrogen peroxide (2ml), under room temperature, reaction is spent the night, and after thin-layer chromatography detection reaction, cancellation adds water, ethyl acetate extraction, merges organic phase, after saturated nacl aqueous solution washing, after anhydrous sodium sulfate drying, filtration is spin-dried for to obtain white solid (25mg, 80%), i.e. formula 10 compounds.
Formula 10 compounds: 1h NMR (300MHz, CDCl 3): δ 6.70 – 6.33 (m, 1H), 5.35 (s, 1H), 4.54 (dt, J=17.2,8.5Hz, 2H), 4.36 – 4.12 (m, 1H), 3.53 (s, 1H), 3.36 – 2.97 (m, 1H), 2.42 – 2.05 (m, 2H), 2.01 (s, 1H).
The preparation of embodiment 11.N-ethyl-3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) propionic acid amide (formula 11 compounds)
Step 1-10 is with embodiment 10
Synthesizing of step 11,3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) propionic acid (formula 11-1 compound)
By formula 10-10 compound (223mg, 1.04mmol) be dissolved in 3mL ethanol and 3mL water, add 3mL (30%) sodium hydroxide solution, be warmed up to 80 DEG C, reaction is spent the night, after thin-layer chromatography detection reaction, revolve ethanol, add water and acetic acid ethyl dissolution after, ice bath, adjusts pH=1-2 with 1N hydrochloric acid, ethyl acetate extraction, merge organic phase, after saturated sodium-chloride washing, after anhydrous sodium sulfate drying, filter, be spin-dried for to obtain faint yellow solid (235mg, 97%), i.e. formula 11-1 compound.Formula 11-1 compound: LC-MS:257.1[M+H] +.
Synthesizing of step 12, N-ethyl-3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) propionic acid amide (formula 11 compounds)
By formula 11-1 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), ethamine (0.248mL, 0.495mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (30mg, 46%), i.e. formula 11 compounds.
Formula 11 compounds: 1h NMR (400MHz, CDCl 3) δ 6.52 (q, J=8.4Hz, 2H), 5.36 (s, 1H), 4.63 – 4.43 (m, 3H), 4.23 (dd, J=8.9,5.2Hz, 1H), 3.60 – 3.40 (m, 1H), 3.34 – 3.16 (m, 3H), 3.16 – 3.01 (m, 1H), 2.26 – 2.01 (m, 3H), 2.01 – 1.85 (m, 1H), 1.17 – 1.02 (m, 3H).
The preparation of embodiment 12.N-methyl-3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) propionic acid amide (formula 12 compounds)
Step 1-10 is with embodiment 10
Step 11 is with embodiment 11
Synthesizing of step 12, N-methyl-3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl) propionic acid amide (formula 12 compounds)
By formula 11-1 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), methylamine (tetrahydrofuran solution of 2M) (0.25mL, 0.50mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (27mg, 43%), i.e. formula 12 compounds.LC-MS:248.1[M+H] +.
The preparation of embodiment 13.3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl)-N-cyclopropyl propionic acid amide (formula 13 compounds)
Step 1-10 is with embodiment 10
Step 11 is with embodiment 11
Synthesizing of step 12,3-(1,2,7,8-tetrahydro benzo [1,2-b:4,3-b'], two furans-1-yl)-N-cyclopropyl propionic acid amide (formula 13 compounds)
By formula 11-1 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), cyclopropylamine (33mg, 0.57mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (57mg, 84%), i.e. formula 13 compounds.LC-MS:274.1[M+H] +.
The preparation of embodiment 14.3-(2,6-dihydro-1H-furans [3,2-e] indoles-8-yl) propionic acid amide (formula 14 compounds)
The iodo-5-of step 1:4-nitro-2,3-dihydro melatonin (formula 14-1 compound) synthetic
Formula 10-2 compound (100mg, 0.406mmol) is dissolved in Glacial acetic acid, slowly drips 68% nitric acid (1ml), add stirring at room temperature 5 hours, the ethyl acetate that adds water, organic layer washs with sodium bicarbonate, saturated common salt water washing, dried over sodium sulfate, be spin-dried for, column chromatography, obtains yellow solid (70mg, 68%), i.e. formula 14-1 compound.Formula 14-1 compound: LC-MS:314.0[M+Na] +.
The iodo-5-of step 2:4-amino-2,3-dihydro melatonin (formula 14-2 compound) synthetic
Formula 14-1 compound (29mg, 0.1mmol) is dissolved in acetic acid 90.5ml) in, add iron powder (11mg, 0.2mmol), add, 80 degrees Celsius are stirred 3 hours, filter, filter cake washs with sodium bicarbonate aqueous solution, and mother liquor regulates pH to 9 with 1N sodium hydroxide, dichloromethane extraction, organic layer saturated common salt water washing, dried over sodium sulfate, is spin-dried for column chromatography and obtains gray solid (13mg, 50%), i.e. formula 14-2 compound.Formula 14-2 compound: LC-MS:284.0[M+Na] +.
Step 3: ethyl 4-((4-iodo-2,3-dihydro melatonin-5-yl) amino) but-2-ene acid esters (formula 14-3 compound) synthetic
Formula 14-2 compound (104mg, 0.4mmol) is dissolved in acetonitrile (1ml), adds salt of wormwood (105mg, 0.8mmol) with bromo ethyl crotonate (120mg, 0.6mmol), add stirred overnight at room temperature, ethyl acetate adds water, organic layer saturated common salt water washing, dried over sodium sulfate, is spin-dried for, and column chromatography obtains brown oily liquids, it is formula 14-3 compound (100mg, 70%).Formula 14-3 compound: LC-MS:374.0[M+H] +.
Step 4: ethyl 2-(2,6-dihydro-1H-furo [3,2-e] indoles-8-yl) acetic ester (formula 14-4 compound) synthetic
Under argon shield, formula 14-3 compound (0.198, 0.53mmol) be dissolved in N, in dinethylformamide: water=9:1 (2ml), add tetran-butylphosphonium bromide amine (0.24g, 0.77mmol), triethylamine (0.31g, 3mmol), 2, 3-diphenylphosphine Palladous chloride (0.04g, 0.05mmol), add, 80 degrees Celsius are spent the night, ethyl acetate adds water, organic layer saturated common salt water washing, dried over sodium sulfate, , be spin-dried for, it is gray solid that column chromatography obtains product, be formula 14-4 compound (0.124g, 90%). formula 14-4 compound: LC-MS:246.1[M+H] +.
Synthesizing of step 5:2-(2,6-dihydro-1H-furo [3,2-e] indoles-8-yl) ethanol (formula 14-5 compound)
Formula 14-4 compound (43.4mg, 0.2mmol) is dissolved in tetrahydrofuran (THF) (0.5ml), slowly adds Lithium Aluminium Hydride (16mg under ice bath, 0.4mmol), add, stirring at room temperature 2 hours, uses saturated ammonium chloride cancellation under ice bath, ethyl acetate extraction, saturated common salt water washing, dried over sodium sulfate, obtains gray solid, it is formula 14-5 compound (20.6mg, 51%).Formula 14-5 compound: LC-MS:204.1[M+H] +.
Synthesizing of step 6:2-(2,6-dihydro-1H-furo [3,2-e] indoles-8-yl) ethyl methane sulfonate ester (formula 14-6 compound)
Formula 14-5 compound (203mg, 1mmol) be dissolved in methylene dichloride (1ml), add triethylamine (150mg, 1.5mmol), under ice bath, drip methylsulfonyl chloride (171mg, 1.5mmol), add stirring at room temperature 6h, add water and add methylene chloride, organic layer saturated common salt water washing, dried over sodium sulfate, is spin-dried for to obtain formula 9-6 compound (220mg, 80%).Formula 14-6 compound: LC-MS:382.1[M+H] +.
Synthesizing of step 7:3-(2,6-dihydro-1H-furo [3,2-e] indoles-8-yl) propionitrile (formula 14-7 compound)
Formula 14-6 compound (315mg, 1.12mmol) be dissolved in DMF (10ml), add sodium cyanide (84mg, 1.67mmol), add stirring at room temperature 12h, the cancellation that adds water reaction, adds ethyl acetate extraction, organic layer saturated common salt water washing, dried over sodium sulfate, is spin-dried for to obtain formula 14-7 compound (190mg, 80%).Formula 14-7 compound: LC-MS:213.1[M+H] +.
Synthesizing of step 8:3-(2,6-dihydro-1H-furo [3,2-e] indoles-8-yl) propionitrile (formula 14 compounds)
Formula 14-7 compound (15mg, 0.073mmol) be dissolved in DMSO (2ml), add salt of wormwood (20mg, 0.15mmol), add 30% (massfraction) hydrogen peroxide (0.5ml), add stirring at room temperature 2h, the cancellation that adds water reaction, adds ethyl acetate extraction, organic layer saturated common salt water washing, dried over sodium sulfate, is spin-dried for to obtain formula 9 compounds (15mg, 90%).Formula 14 compounds: LC-MS:230.1[M+H] +.
Embodiment 15.N-ethyl-2, the preparation of the fluoro-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) propionic acid amide (formula 15 compounds)
Step 1:2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-nitrile (formula 15-2 compound) synthetic
Formula 15-1 compound (174mg, 1mmol, its synthetic method is shown in US6034239A1, 2000) be dissolved in dry DME (glycol dimethyl ether) (6mL), add TosMIC (to Methyl benzenesulfonyl methyl isonitrile) (648mg, 2.2mmol), ice-water bath is cooled to 0 DEG C, add ethanol (0.08mL, 2.2mmol) and potassium tert.-butoxide (246mg, 2.2mmol), heat up 60 DEG C and stir 18h, heat up 60 DEG C and stir 18h, cooling, the concentrated organic solvent of removing, add acetic acid ethyl dissolution residual, saturated common salt water washing, dried over sodium sulfate, be spin-dried for, column chromatography, obtain yellow solid, be formula 10-2 compound (176mg, 95%).Formula 15-2 compound: LC-MS:186.10[M+H] +.
Step 2:2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-aldehyde (formula 15-3 compound) synthetic
Formula 15-2 compound (185mg, 1mmol) is dissolved in dry tetrahydrofuran (10mL), is cooled to-78 DEG C, drip diisobutyl aluminium hydride (DIBAL-H) hexane solution (volumetric molar concentration is 1M) (1mL, 1mmol), insulated and stirred 1h, add methyl alcohol cancellation reaction, add 200-300 order silica gel (1g), stir 10min, filter, concentrated, obtain yellow solid, i.e. formula 15-3 compound (188mg, 100%).Formula 10-3 compound: LC-MS:188.1[M+H] +.
Step 3:2, the fluoro-3-hydroxyl-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) ethyl propionate (formula 15-4 compound) synthetic
Formula 15-3 compound (2g, 10.63mmol) is dissolved in dry toluene (30mL), adds 2-bromo-2,2-ethyl difluoro (1.83g, 9mmol), zinc powder (764mg, 11.7mmol), heat up 120 DEG C and stir 12h, after reacting completely, add 1M (volumetric molar concentration) hcl acidifying, filter, separate organic phase, water is extracted with ethyl acetate, and merges organic phase, sodium bicarbonate washing, saturated common salt water washing, dried over sodium sulfate, is spin-dried for, column chromatography, obtain yellow solid, i.e. formula 15-4 compound (2.5g, 75%).Formula 15-4 compound: LC-MS:313.1[M+H] +.
Step 4:2, the fluoro-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) ethyl propionate (formula 15-5 compound) synthetic
Formula 15-4 compound (1.59g, 5.1mmol) be dissolved in dry DMF (N, dinethylformamide) (20mL), under argon shield, add DBU (1, 8-diazacyclo [5, 4, 0] hendecene-7) (3mL, 20.4mmol), dithiocarbonic anhydride (3mL, 51mmol), stir 1h, add methyl iodide (3.2mL, 51mmol) stir 1h, after reacting completely, except desolventizing, add water (50mL), be extracted with ethyl acetate, merge organic phase, sodium bicarbonate washing, saturated common salt water washing, dried over sodium sulfate, be spin-dried for, obtain crude product yellow solid (2.14g, 100%).LC-MS:403.1[M+H] +.
Above-mentioned crude product (2.14g; 5.1mmol) be dissolved in dry dioxane (30mL); under argon shield, add diphenylphosphine oxygen (1.05g, 5.1mmol) and peroxy tert-butyl alcohol (460 μ L; 2.3mmol); backflow 7h, after reacting completely, except desolventizing, column chromatography for separation obtains white solid; it is formula 15-5 compound (1.1g, 71%).Formula 15-5 compound: LC-MS:297.1[M+H] +.
Step 5:2, the fluoro-3-hydroxyl-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) ethyl propionate (formula 15-6 compound) synthetic
Formula 15-5 compound (1g, 3.37mmol) be dissolved in ethanol (10mL), add 30% (massfraction) aqueous sodium hydroxide solution (2mL), 80 DEG C of reaction 12h heat up, after reacting completely, pour in frozen water, add 1M (volumetric molar concentration) hcl acidifying, filter, dry, obtain faint yellow solid, i.e. formula 15-6 compound (0.9g, 99%).Formula 15-6 compound: LC-MS:, 267.2[M-H] +.
Step 6:N-ethyl-2, the fluoro-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) propionic acid amide (formula 15 compounds) synthetic
By formula 15-5 compound (66mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), ethamine (0.248mL, 0.495mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (62mg, 86%), i.e. formula 15 compounds.
Formula 15 compounds: LC-MS:295.1[M+H] +.
Embodiment 16.N-propyl group-2, the preparation of the fluoro-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) propionic acid amide (formula 16 compounds)
Step 1-5 is with embodiment 15
Step 6:N-propyl group-2, the fluoro-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) propionic acid amide (formula 16 compounds) synthetic
By formula 15-5 compound (66mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), propylamine (30mg, 0.495mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (65mg, 90%), i.e. formula 16 compounds.
Formula 16 compounds: LC-MS:310.1[M+H] +.
Embodiment 17.N-butyl-2, the preparation of the fluoro-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) propionic acid amide (formula 17 compounds)
Step 1-5 is with embodiment 15
Step 6:N-butyl-2, the fluoro-3-of 2-bis-(2,6,7,8-tetrahydrochysene-1H-indoles [5,4-b] furans-8-yl) propionic acid amide (formula 17 compounds) synthetic
By formula 15-5 compound (66mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), butylamine (36mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (59mg, 74%), i.e. formula 17 compounds.
Formula 17 compounds: LC-MS:324.2[M+H] +.
The preparation of embodiment 18.N-cyclopropyl-2-((2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) oxygen base) ethanamide (formula 18 compounds)
Step 1:2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-alcohol (formula 18-1 compound) synthetic
Formula 18-A compound (174mg, 1mmol, its synthetic method is shown in US6034239A1,2000) be dissolved in methyl alcohol (3mL) and tetrahydrofuran (THF) (6mL), ice-water bath is cooled to 0 DEG C, adds sodium borohydride (57mg, 1.5mmol), stirring at room temperature 6h, add methyl alcohol (10mL) cancellation reaction, organic solvent is removed in decompression, concentrated, add methyl alcohol (5mL), organic solvent is removed in decompression, repeats to add methyl alcohol concentration operation 3 times, obtains yellow solid, it is formula 18-1 compound (176mg, 100%).Formula 18-1 compound: LC-MS:159.10[M-18] +.
Step 2:2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) oxygen base) ethyl acetate (formula 18-2 compound) synthetic
Formula 18-1 compound (352mg, 2mmol) be dissolved in dry DMF (N, dinethylformamide) (10mL), be cooled to 0 DEG C, add salt of wormwood (828mg, 6mmol) and bromoethyl acetate (400mg, 2.4mmol), stirring at room temperature 6h, the cancellation that adds water reaction, the extraction of EA ethyl acetate, merge organic phase, saturated common salt water washing, dried over sodium sulfate, is spin-dried for, column chromatography, obtain yellow solid, i.e. formula 18-2 compound (472mg, 89%).Formula 18-2 compound: LC-MS:263.1[M+H] +.
Step 3:2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) oxygen base) acetic acid (formula 18-3 compound) synthetic
Formula 18-2 compound (472mg, 1.8mmol) be dissolved in ethanol (10mL), add 10% (massfraction) aqueous sodium hydroxide solution (3mL), stirring at room temperature 2h, after reacting completely, add 1M (volumetric molar concentration) hcl acidifying, filter, dry, obtain white solid, it is formula 18-3 compound (400mg, 95%).Formula 18-3 compound: LC-MS:235.1[M+H] +.
Synthesizing of step 4:N-cyclopropyl-2-((2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) oxygen base) ethanamide (formula 18 compounds)
By formula 18-3 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), cyclopropylamine (36mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (55mg, 81%), i.e. formula 18 compounds.
Formula 18 compounds: LC-MS:274.2[M+H] +.
The preparation of embodiment 19.N-ethyl-2-((2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) oxygen base) ethanamide (formula 19 compounds)
Step 1-3 is with embodiment 18
Synthesizing of step 4:N-ethyl-2-((2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) oxygen base) ethanamide (formula 19 compounds)
By formula 18-3 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), ethamine (27mg, 0.602mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (49mg, 76%), i.e. formula 19 compounds.
Formula 19 compounds: LC-MS:262.15[M+H] +.
The preparation of embodiment 20.N-cyclopropyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 20 compounds)
Synthesizing of the bromo-3-of step 1.2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid (formula 20-1 compound)
By formula 3-1 compound (860mg, 3.64mmol) be dissolved in toluene (10mL), be chilled to 0 DEG C, add successively red phosphorus (148mg, 4.78mmol) and bromine (1mL, 18.7mmol), reaction solution is warmed up to 80 DEG C, reacts 3 hours, thin-layer chromatography detection reaction is complete, pour reaction solution into aqueous solution of sodium bisulfite, add solid sodium bicarbonate neutralization, separate organic phase, aqueous phase as acidified, filter, obtain 1.06g yellow solid (being formula 20-1 compound), productive rate is 92%.Formula 20-1 compound: LC-MS:311.10[M+H] +.
Synthesizing of step 2.2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid (formula 20-2 compound)
By formula 20-1 compound (654mg, 2.1mmol) be dissolved in Virahol (10mL), drip 10% (massfraction) aqueous sodium hydroxide solution (3mL), reaction solution is warmed up to 85 DEG C, back flow reaction 6h, thin-layer chromatography detection reaction is complete, by the concentrated reaction solution organic solvent of removing, acidifying, filters and obtains 501mg white solid (being formula 20-2 compound), and productive rate is 96%.Formula 20-2 compound: LC-MS:240.10[M-18] +. synthesizing of step 3:N-cyclopropyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 20 compounds)
By formula 20-2 compound (61mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), cyclopropylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (51mg, 72%), i.e. formula 20 compounds.
Formula 20 compounds: LC-MS:288.2[M+H] +.
The preparation of embodiment 21.N-methyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 21 compounds)
Step 1-2 is with embodiment 20
Synthesizing of step 3:N-methyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 21 compounds)
By formula 20-2 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), methylamine (tetrahydrofuran solution of 2M) (2.46ml, 4.92mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (32mg, 47%), i.e. formula 21 compounds.
Formula 21 compounds: LC-MS:262.15[M+H] +.
The preparation of embodiment 22.N-n-propyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 22 compounds)
Step 1-2 is with embodiment 20
Synthesizing of step 3:N-n-propyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 22 compounds)
By formula 20-2 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), Tri N-Propyl Amine (26.6mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (59mg, 87%), i.e. formula 22 compounds.
Formula 22 compounds: 1h NMR (500MHz, CDCl 3) δ 6.94 (d, J=7.8Hz, 1H), 6.68 – 6.55 (m, 1H), 5.81 (s, 1H), 4.77 – 4.41 (m, 3H), 3.40 – 3.05 (m, 3H), 2.93 – 2.82 (m, 1H), 2.83 – 2.65 (m, 1H), 2.35 (d, J=7.6Hz, 1H), 2.21 (d, J=4.6Hz, 2H), 2.05 (s, 1H), 1.85 – 1.66 (m, 2H), 1.44 (d, J=17.0Hz, 2H), 0.93 – 0.82 (m, 3H); LC-MS:285.13[M+H] +; Purity:89%.
The preparation of the embodiment 23.N-tertiary butyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 23 compounds)
Step 1-2 is with embodiment 20
Synthesizing of the step 3:N-tertiary butyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 23 compounds)
By formula 20-2 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), TERTIARY BUTYL AMINE (34mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (62mg, 92%), i.e. formula 23 compounds.
Formula 23 compounds: 1h NMR (400MHz, CDCl 3) δ 6.95 (d, J=6.9Hz, 1H), 6.62 (dd, J=7.9, 4.6Hz, 1H), 6.08 (s, 1H), 4.64 – 4.41 (m, 2H), 4.14 – 3.96 (m, 1H), 3.39 (d, J=4.6Hz, 1H), 3.26 (dt, J=18.1, 9.0Hz, 1H), 3.12 (td, J=16.1, 9.5Hz, 1H), 2.90 (s, 1H), 2.85 – 2.74 (m, 1H), 2.73 (t, J=5.4Hz, 1H), 2.51 (d, J=5.0Hz, 0H), 2.38 – 2.25 (m, 1H), 2.27 – 2.10 (m, 0H), 1.89 (d, J=51.6Hz, 3H), 1.37 (d, J=1.2Hz, 9H), LC-MS:303.20[M+H] +, Purity:88%.
The preparation of embodiment 24.N-normal-butyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 24 compounds)
Step 1-2 is with embodiment 20
Synthesizing of step 3:N-normal-butyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 24 compounds)
By formula 20-2 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), n-Butyl Amine 99 (34mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (60mg, 89%), i.e. formula 24 compounds.
Formula 24 compounds: 1h NMR (500MHz, CDCl 3) δ 6.94 (d, J=8.2Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 5.37 (s, 1H), 4.69 – 4.43 (m, 2H), 3.34 – 3.07 (m, 4H), 2.97 (s, 1H), 2.93 – 2.79 (m, 1H), 2.78 (d, J=15.2Hz, 1H), 2.21 (t, J=6.5Hz, 3H), 1.76 (dd, J=12.4,3.9Hz, 3H), 1.52 – 1.41 (m, 4H), 1.41 – 1.29 (m, 5H); LC-MS:303.20[M+H] +; Purity:94%
The preparation of embodiment 25.N-sec.-propyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 25 compounds)
Step 1-2 is with embodiment 20
Synthesizing of step 3:N-sec.-propyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 25 compounds)
By formula 20-2 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), Isopropylamine (27mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (53mg, 89%), i.e. formula 25 compounds.
Formula 25 compounds: 1h NMR (500MHz, CDCl 3) δ 6.94 (d, J=7.8Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 5.21 (s, 1H), 4.67 – 4.45 (m, 3H), 4.16 – 3.99 (m, 2H), 3.44 – 3.22 (m, 2H), 3.22 – 3.09 (m, 2H), 2.97 (d, J=7.6Hz, 1H), 2.96 (s, 1H), 2.77 (dd, J=14.8,8.5Hz, 1H), 2.30 – 2.20 (m, 1H), 1.76 (ddd, J=19.1,13.7,7.7Hz, 2H), 1.16-1.13 (m, 6H); LC-MS:285.13[M+H] +; Purity:94%
The preparation of embodiment 26.N-propargyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 26 compounds)
Step 1-2 is with embodiment 20
Synthesizing of step 3:N-propargyl-2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 26 compounds)
By formula 20-2 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), propargylamine (26mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (24mg, 35%), i.e. formula 26 compounds.
Formula 26 compounds: 1h NMR (400MHz, CDCl 3) δ 6.96 (t, J=7.1Hz, 1H), 6.73 (s, 1H), 6.62 (dt, J=9.4,4.7Hz, 1H), 4.63 – 4.44 (m, 2H), 4.25 (d, J=10.0Hz, 1H), 4.15 – 4.00 (m, 3H), 3.41 (d, J=8.5Hz, 1H), 3.32 – 3.19 (m, 1H), 3.18 – 3.02 (m, 1H), 2.92 (dt, J=15.1,7.6Hz, 1H), 2.86 – 2.73 (m, 1H), 2.67 (s, 1H), 2.43 – 2.26 (m, 2H), 1.97 – 1.78 (m, 2H); LC-MS:285.20[M+H] +; Purity:88%
The preparation of the fluoro-3-of embodiment 27.N-methyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 27 compounds)
Synthesizing of the fluoro-3-of step 1:N-methyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 27 compounds)
Formula 21 compounds (68mg, 0.260mmol) are dissolved in dry methylene dichloride, add DAST (diethylin sulfur trifluoride) (210mg, 1.30mmol), 0 degree Celsius of reaction 5h.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (47mg, 69%), i.e. formula 27 compounds.
Formula 27 compounds: LC-MS:264.13[M+H]+.
The preparation of the fluoro-3-of embodiment 28.N-cyclopropyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 28 compounds)
Synthesizing of the fluoro-3-of step 1:N-cyclopropyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 28 compounds)
Formula 20 compounds (100mg, 0.348mmol) are dissolved in dry methylene dichloride, add DAST (diethylin sulfur trifluoride) (280mg, 1.74mmol), 0 degree Celsius of reaction 5h.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (67mg, 66%), i.e. formula 28 compounds.
Formula 28 compounds: LC-MS:264.13[M+H]+.
The preparation of the fluoro-3-of embodiment 29.N-n-propyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 29 compounds)
Synthesizing of the fluoro-3-of step 1:N-n-propyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 29 compounds)
Formula 22 compounds (100mg, 0.348mmol) are dissolved in dry methylene dichloride, add DAST (diethylin sulfur trifluoride) (280mg, 1.74mmol), 0 degree Celsius of reaction 5h.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (67mg, 66%), i.e. formula 29 compounds.
Formula 29 compounds: LC-MS:264.13[M+H]+.
The preparation of the fluoro-3-of the embodiment 30.N-tertiary butyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 30 compounds)
Synthesizing of the fluoro-3-of the step 1:N-tertiary butyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 30 compounds)
Formula 23 compounds (106mg, 0.348mmol) are dissolved in dry methylene dichloride, add DAST (diethylin sulfur trifluoride) (280mg, 1.74mmol), 0 degree Celsius of reaction 5h.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (97mg, 91%), i.e. formula 30 compounds.
Formula 30 compounds: LC-MS:306.18[M+H]+.
The preparation of the fluoro-3-of embodiment 31.N-normal-butyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 31 compounds)
Synthesizing of the fluoro-3-of step 1:N-normal-butyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 31 compounds)
Formula 24 compounds (106mg, 0.348mmol) are dissolved in dry methylene dichloride, add DAST (diethylin sulfur trifluoride) (280mg, 1.74mmol), 0 degree Celsius of reaction 5h.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (90mg, 85%), i.e. formula 31 compounds.
Formula 31 compounds: LC-MS:306.18[M+H]+.
The preparation of the fluoro-3-of embodiment 32.N-sec.-propyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 32 compounds)
Synthesizing of the fluoro-3-of step 1:N-sec.-propyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 32 compounds)
Formula 25 compounds (100mg, 0.348mmol) are dissolved in dry methylene dichloride, add DAST (diethylin sulfur trifluoride) (280mg, 1.74mmol), 0 degree Celsius of reaction 5h.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (90mg, 85%), i.e. formula 32 compounds.
Formula 32 compounds: LC-MS:292.18[M+H]+.
The preparation of the fluoro-3-of embodiment 33.N-propargyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 33 compounds)
Synthesizing of the fluoro-3-of step 1:N-propargyl-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 33 compounds)
Formula 26 compounds (99mg, 0.348mmol) are dissolved in dry methylene dichloride, add DAST (diethylin sulfur trifluoride) (280mg, 1.74mmol), 0 degree Celsius of reaction 5h.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (79mg, 79%), i.e. formula 33 compounds.
Formula 33 compounds: LC-MS:288.18[M+H]+.
Embodiment 34S-2, the preparation of the fluoro-N-of 2-bis-(2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) ethyl) propionic acid amide (formula 34 compounds)
Operation is with embodiment 1, and difference is that formula 34-1 compound is chipal compounds (its building-up process is referring to EP1792899), obtains product 28mg (being formula 34 compounds), yield 27%.
Formula 34 compounds: 1h NMR (400MHz, CDCl 3) δ 6.95 (d, J=8.0Hz, 1H), 6.62 (d, J=8.1Hz, 1H), 6.32 (s, 1H), 4.56 (ddt, J=18.3,16.7,5.3Hz, 2H), 3.48 – 3.34 (m, 2H), 3.21 (d, J=9.0Hz, 2H), 3.16 – 3.03 (m, 1H), 3.00 – 2.86 (m, 1H), 2.83 (dd, J=33.0,7.3Hz, 2H), 2.30 (dd, J=12.8,6.4Hz, 1H), 2.05 (d, J=5.2Hz, 1H), 1.87 – 1.71 (m, 5H); Ee=98%.
The preparation of embodiment 35S-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 35 compounds)
Synthetic (the formula 35-2 compound) of step 1.S-2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) ethanol
Under Ar protection, lithium aluminum hydride (134mg, 3.54mmol) is dissolved in to 10mL tetrahydrofuran (THF), ice bath is chilled to 0 DEG C, slowly adds formula 35-1 compound (290mg, 1.18mmol; Its synthetic method is shown in WO2010/45565) tetrahydrofuran solution 5mL, room temperature reaction 1-2h, thin-layer chromatography reacts completely, add the dilution of 5mL tetrahydrofuran (THF), in ice bath, add successively water 0.2mL, sodium hydroxide (15%, mass percent concentration) aqueous solution 0.2mL, stir 10min, add again 0.6mL water, stirring at room temperature 15min.Anhydrous sodium sulfate drying, concentrated, obtain brown jelly 0.24g (being formula 35-2 compound), yield 100%.
Formula 35-2 compound: 1h NMR (400MHz, CDCl 3) δ 6.93 (t, J=15.9Hz, 1H), 6.62 (d, J=7.9Hz, 1H), 4.66 – 4.42 (m, 2H), 3.90 – 3.65 (m, 2H), 3.26 (dt, J=15.0, 9.7Hz, 2H), 3.19 – 3.05 (m, 1H), 2.99 – 2.82 (m, 1H), 2.83 – 2.67 (m, 1H), 2.27 (dtd, J=12.6, 8.3, 6.4Hz, 1H), 2.11 (dtd, J=13.5, 7.5, 4.1Hz, 1H), 1.92 – 1.74 (m, 1H), 1.68 (dddd, J=13.4, 10.1, 6.8, 5.4Hz, 1H). step 2.S-2-(2, 6, 7, 8-tetrahydrochysene-1H-indeno [5, 4-b] furans-8-yl) synthetic (the formula 35-3 compound) of ethyl methane sulfonate ester (YF-259-31)
Under Ar protection; by formula 35-2 compound (155mg; 0.76mmol) be dissolved in dry tetrahydrofuran (10mL), ice bath is chilled to 0 DEG C, adds triethylamine (123mg; 1.22mmol; 1.6eq), drip methylsulfonyl chloride (105mg, 0.91mmol; 1.2eq); drip complete room temperature reaction 1h, thin-layer chromatography reacts completely, and adds sodium bicarbonate aqueous solution cancellation reaction; ethyl acetate extraction; the washing of organic phase saturated common salt, anhydrous sodium sulfate drying, concentrated; obtain jelly 185mg (being formula 35-3 compound), productive rate is 73%.
Formula 35-3 compound: LC-MS:283.20[M+H] +.
Synthetic (the formula 35-4 compound) of step 3.S-3-(2,6,7,8-tetrahydrochysene-1H-indenes [5,4-b] furans-8-yl) propionitrile
50mL N, dinethylformamide dissolution type 35-3 compound crude product (8g, 28mmol, 1eq.), add sodium cyanide (4.9g, 100mmol, 5eq.), 85 DEG C of reactions are spent the night, and it is complete that thin-layer chromatography (sherwood oil: ethyl acetate=2:1) detects primitive reaction, pours in trash ice, ethyl acetate extraction, washing, saturated sodium-chloride are washed organic phase, and anhydrous sodium sulfate drying is concentrated, obtain crude product, column chromatography for separation, obtains the colourless jelly of 5.5g (being formula 35-4 compound), and productive rate is 91%.
Formula 35-4 compound: 1h NMR (400MHz, CDCl 3) δ 6.97 (d, J=8.0Hz, 1H), 6.64 (d, J=8.0Hz, 1H), 4.74 – 4.37 (m, 2H), 3.30 (ddd, J=16.3,8.6,3.8Hz, 1H), 3.25 – 3.05 (m, 2H), 2.95 – 2.73 (m, 2H), 2.48 – 2.36 (m, 2H), 2.36 – 2.24 (m, 1H), 2.24 – 2.11 (m, 1H), 1.86 – 1.71 (m, 2H).
Synthesizing of step 4.S-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 35 compounds)
By formula 35-4 compound (860mg, 4.03mmol) be dissolved in DMSO (10mL), slowly add salt of wormwood (1.11mg, 8.06mmol), ice bath is chilled to 0 DEG C, drip hydrogen peroxide (30%) (2mL), stirring at room temperature 2 hours, thin-layer chromatography detection reaction is complete, the cancellation that adds water reaction, dichloromethane extraction 3 times, saturated common salt washing 1 time, dried over sodium sulfate, 200～300 order silica gel column chromatographies obtain white solid 890mg (being formula 35 compounds), yield 97%.
Formula 35 compounds: 1h NMR (400MHz, CDCl 3) δ 6.94 (d, J=7.9Hz, 1H), 6.62 (d, J=7.8Hz, 1H), 5.36 (s, 2H), 4.65 – 4.43 (m, 2H), 3.23 (ddd, J=41.2,15.7,7.6Hz, 3H), 2.94 – 2.69 (m, 2H), 2.33 – 2.14 (m, 4H), 1.83 – 1.71 (m, 2H); LC-MS:232.10[M+H] +; Ee=98%.
The preparation of embodiment 36S-N-ethyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 36 compounds)
Step 1-3 is with embodiment 35
Synthesizing of step 4.S-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid (formula 36-1 compound)
10mL ethanol and water mixed solvent (volume ratio is 1:1) dissolution type 35-4 compound (100mg, 0.47mmol, 1eq.), 80 DEG C of reactions are spent the night, it is complete that thin-layer chromatography detects primitive reaction, pour in trash ice dichloromethane extraction, saturated common salt water washing organic phase into, anhydrous sodium sulfate drying, concentrated, obtain yellow colloidal crude 210mg (being formula 36-1 compound), productive rate is 100%.Formula 36-1 compound: LC-MS:232.15[M+H] +.
Synthesizing of step 5.S-N-ethyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 36 compounds)
By formula 36-1 compound (143mg, 0.62mmol) be dissolved in anhydrous methylene chloride (10mL), add DMAP (112mg, 0.92mmol), ethamine (42mg, 0.92mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (176mg, 0.92mmol), stirring at room temperature 2 hours, add water, dichloromethane extraction 3 times, saturated common salt washing 1 time, dried over sodium sulfate, 200～300 order silica gel column chromatographies obtain faint yellow solid 140mg (being formula 36 compounds), yield 87%.
Formula 36 compounds: 1h NMR (400MHz, CDCl 3) δ 7.22 (s, 1H), 6.89 (d, J=8.0Hz, 1H), 6.56 (d, J=8.0Hz, 1H), 5.44 (s, 2H), 4.62 – 4.38 (m, 2H), 3.33 – 3.01 (m, 5H), 2.75 (dtd, J=21.9,15.4,6.8Hz, 2H), 2.26 – 2.04 (m, 2H), 1.71 (dd, J=7.2,5.6Hz, 2H), 1.08 (t, J=7.3Hz, 3H); LC-MS:262.20[M+H] +; Ee=98%.
The preparation of embodiment 37.2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 37 compounds)
Step 1-2 is with embodiment 20
Synthesizing of step 3:2-hydroxyl-3-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 37 compounds)
By formula 20-2 compound (58mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), ammoniacal liquor (2ml, 49.2mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (39mg, 69%), i.e. formula 37 compounds.
Formula 37 compounds: LC-MS:248.15[M+H] +.
the fluoro-3-of embodiment 38.2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amidethe preparation of (formula 38 compounds)
Synthesizing of the fluoro-3-of step 1:2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 38 compounds)
Formula 37 compounds (86mg, 0.348mmol) are dissolved in dry methylene dichloride, add DAST (diethylin sulfur trifluoride) (280mg, 1.74mmol), 0 degree Celsius of reaction 5h.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (69mg, 79%), i.e. formula 38 compounds.
Formula 38 compounds: LC-MS:306.18[M+H]+.
embodiment 39.n-cyclopropyl- the bromo-3-of 2-(2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amidethe preparation of (formula 39 compounds)
By formula 20-1 compound (77mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), cyclopropylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (74mg, 85%), i.e. formula 39 compounds: LC-MS:351.3[M+H] +.
The preparation of embodiment 40.N-cyclopropyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 40 compounds)
Synthesizing of the bromo-3-of step 1.2-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid (formula 40-1 compound)
By formula 36-1 compound (860mg, 3.64mmol) be dissolved in toluene (10mL), be chilled to 0 DEG C, add successively red phosphorus (148mg, 4.78mmol) and bromine (1mL, 18.7mmol), reaction solution is warmed up to 80 DEG C, reacts 3 hours, thin-layer chromatography detection reaction is complete, pour reaction solution into aqueous solution of sodium bisulfite, add solid sodium bicarbonate neutralization, separate organic phase, aqueous phase as acidified, filter, obtain 1.06g yellow solid (being formula 40-1 compound), productive rate is 92%.Formula 40-1 compound: LC-MS:311.10[M+H] +.
Synthesizing of step 2.2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid (formula 40-2 compound)
By formula 40-1 compound (654mg, 2.1mmol) be dissolved in Virahol (10mL), drip 10% (massfraction) aqueous sodium hydroxide solution (3mL), reaction solution is warmed up to 85 DEG C, back flow reaction 6h, thin-layer chromatography detection reaction is complete, by the concentrated reaction solution organic solvent of removing, acidifying, filters and obtains 501mg white solid (being formula 40-2 compound), and productive rate is 96%.Formula 40-2 compound: LC-MS:240.10[M-18] +. synthesizing of step 3:N-cyclopropyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 40 compounds)
By formula 40-2 compound (61mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), cyclopropylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (58mg, 82%), i.e. formula 40 compounds: LC-MS:288.2[M+H] +.
The preparation of the bromo-3-of embodiment 41.N-cyclopropyl-2-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 41 compounds)
Formula 20-1 compound (77mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), cyclopropylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (73mg, 85%), i.e. formula 41 compounds.
Formula 41 compounds: LC-MS:351.2[M+H] +.
Embodiment 42. (S)-N-cyclopropyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) preparation process 1:2-((S)-2,6,7 of propionic acid amide (formula 42 compounds), 8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) preparation of acetaldehyde (formula 42-1 compound)
(COCl) 2(oxalyl chloride) (1.72g, 13.51mmol) be dissolved in dry methylene dichloride (20mL), be chilled to-78 degrees Celsius, be added dropwise to DMSO (dimethyl sulfoxide (DMSO)) (4.75g, 16.89mmol), add reaction 1 hour, be added dropwise to formula 35-2 compound (2.3g, dichloromethane solution (20mL) 11.26mmol), finish-78 degrees Celsius of reaction 1-2 hour, drip triethylamine (3.42g, 33.87mmol), finish-78 degrees Celsius of reaction 1-2 hour, naturally rise to room temperature, pour in frozen water, dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, obtain colorless oil (2.2g, 96%), be formula 42-1 compound: LC-MS:203.10[M+H] +.
Step 2:(S) preparation of-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionitrile (formula 42-2 compound)
(S)-bis-(3, 5-dimethyl is stupid) (synthetic method is referring to document Journal of Organic Chemistry for (pyrrolidin-2-yl) methyl alcohol, 2007, 72 (18): 7066-7069) (188mg, 0.608mmol), 2-methylphenylboronic acid (71.4mg, 0.202mmol) be dissolved in dry toluene (25mL), be heated to 145 degrees Celsius of reaction 3-4 hour, be chilled to 60 degrees Celsius, underpressure distillation concentration of reaction solution is to 5mL, constantly add toluene (3 × 5mL) to repeat underpressure distillation three times, be chilled to room temperature, argon shield, the concentrated colourless solution that obtains, be chilled to-25 degrees Celsius, be added dropwise to bis trifluoromethyl semi-annular jade pendant imide (2.5Ml, 0.2M toluene solution, 0.5mmol), after 10 minutes, under 0 degrees celsius, above-mentioned solution is added to triphen oxygen phosphorus (293mg, 1.05mmol) in, react 10 minutes to dissolving, add trimethyl silicane nitrile (0.752mL, 5.64mmol) with formula 42-1 compound (1.01g, toluene solution (5mL) 5mmol), react after 1-2 hour, 0 degree Celsius is continued reaction 1-2 hour, after reacting completely, add 2M hydrochloric acid soln (5mL) and ethyl acetate (5mL), react 2 hours, ethyl acetate extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, obtain colorless oil (0.83g, 72%, ee:95%), be formula 42-2 compound: LC-MS:230.10[M+H] +.
Step 3:(S) preparation of-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) methyl propionate (formula 42-3 compound)
Formula 42-2 compound (1.5g, 6.54mmol) be dissolved in methyl alcohol (25mL), add 80 degrees Celsius of reactions of concentrated hydrochloric acid (2mL) 24 hours, after reacting completely, concentrated except desolventizing, obtain crude product oily matter (1.65g, 96%), i.e. formula 42-3 compound: LC-MS:263.10[M+H] +.
Step 4:(S) preparation of-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) methyl propionate (formula 42-4 compound)
Formula 42-3 compound (1.65g, 6.28mmol) is dissolved in methyl alcohol (36mL) and water (12mL), adds lithium hydroxide (396mg, 9.42mmol), 65 degrees Celsius are reacted 10 hours, after reacting completely, concentrated except desolventizing, pour in frozen water, be acidified to pH=1-2, filter, dry to obtain faint yellow solid (1.55g, 99%), i.e. formula 42-4 compound: LC-MS:249.10[M+H] +.
Step 5:(S) preparation of-N-cyclopropyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 42 compounds)
By formula 42-4 compound (61mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), cyclopropylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (58mg, 82%), i.e. formula 42 compounds: LC-MS:288.2[M+H] +.
Embodiment 43. (R)-N-cyclopropyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) the preparation process 1:(R of propionic acid amide (formula 43 compounds))-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) preparation of propionitrile (formula 43-1 compound)
(R)-bis-(3, 5-dimethyl is stupid) (synthetic method is referring to document Journal of Organic Chemistry for (pyrrolidin-2-yl) methyl alcohol, 2007, 72 (18): 7066-7069) (188mg, 0.608mmol), 2-methylphenylboronic acid (71.4mg, 0.202mmol) be dissolved in dry toluene (25mL), be heated to 145 degrees Celsius of reaction 3-4 hour, be chilled to 60 degrees Celsius, underpressure distillation concentration of reaction solution is to 5mL, constantly add toluene (3 × 5mL) to repeat underpressure distillation three times, be chilled to room temperature, argon shield, the concentrated colourless solution that obtains, be chilled to-25 degrees Celsius, be added dropwise to bis trifluoromethyl semi-annular jade pendant imide (2.5Ml, 0.2M toluene solution, 0.5mmol), after 10 minutes, under 0 degrees celsius, above-mentioned solution is added to triphen oxygen phosphorus (293mg, 1.05mmol) in, react 10 minutes to dissolving, add trimethyl silicane nitrile (0.752mL, 5.64mmol) with formula 42-1 compound (1.01g, toluene solution (5mL) 5mmol), react after 1-2 hour, 0 degree Celsius is continued reaction 1-2 hour, after reacting completely, add 2M hydrochloric acid soln (5mL) and ethyl acetate (5mL), react 2 hours, ethyl acetate extraction, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, obtain colorless oil (0.83g, 72%, ee:95%), be formula 43-1 compound: LC-MS:230.10[M+H] +.
Step 2:(R) preparation of-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) methyl propionate (formula 43-2 compound)
Formula 43-1 compound (1.5g, 6.54mmol) be dissolved in methyl alcohol (25mL), add 80 degrees Celsius of reactions of concentrated hydrochloric acid (2mL) 24 hours, after reacting completely, concentrated except desolventizing, obtain crude product oily matter (1.65g, 96%), i.e. formula 43-2 compound: LC-MS:263.10[M+H] +.
Step 3:(R) preparation of-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) methyl propionate (formula 43-3 compound)
Formula 43-2 compound (1.65g, 6.28mmol) is dissolved in methyl alcohol (36mL) and water (12mL), adds lithium hydroxide (396mg, 9.42mmol), 65 degrees Celsius are reacted 10 hours, after reacting completely, concentrated except desolventizing, pour in frozen water, be acidified to pH=1-2, filter, dry to obtain faint yellow solid (1.55g, 99%), i.e. formula 43-3 compound: LC-MS:249.10[M+H] +.
Step 4:(R) preparation of-N-cyclopropyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 43 compounds)
By formula 43-3 compound (61mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), cyclopropylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (58mg, 82%), i.e. formula 43 compounds: LC-MS:288.2[M+H] +.
The preparation of embodiment 44.N-propargyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 44 compounds)
By formula 40-2 compound (61mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), propargylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (58mg, 82%), i.e. formula 44 compounds: LC-MS:288.2[M+H] +.
The preparation of embodiment 45. (S)-N-propargyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 45 compounds)
By formula 42-4 compound (61mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), propargylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (58mg, 82%), i.e. formula 45 compounds: LC-MS:288.2[M+H] +.
The preparation of embodiment 46. (R)-N-propargyl-2-hydroxyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 46 compounds)
By formula 43-3 compound (61mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), propargylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (58mg, 82%), i.e. formula 46 compounds: LC-MS:288.2[M+H] +.
The preparation of embodiment 47.N-propargyl-2-sulfydryl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 47 compounds)
The preparation of step 1:2-sulfydryl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid (formula 47-1 compound)
By water-soluble formula 20-1 compound (1.3g, 4.18mmol), add Sodium sulfhydrate (703mg, 12.5mmol) ,-5 degrees Celsius of reaction 12h.After thin-layer chromatography detection reaction, dichloromethane extraction, merges after organic phase, saturated common salt water washing, and anhydrous sodium sulfate drying, filtration is spin-dried for, and obtains faint yellow solid (906mg, 82%), i.e. formula 47-1 compound: LC-MS:265.3[M+H] +.
The preparation of step 2:N-propargyl-2-sulfydryl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 47 compounds)
By formula 47-1 compound (66mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), propargylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (68mg, 91%), i.e. formula 47 compounds: LC-MS:302.4[M+H] +.
The preparation of embodiment 48.N-propargyl-2-amino-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 48 compounds)
The preparation of step 1:2-azido--3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid (formula 48-1 compound)
Formula 20-1 compound (3.2g, 10.3mmol) is dissolved in DMF, adds sodiumazide (2g, 31mmol), 50 degrees Celsius of reaction 12h.After thin-layer chromatography detection reaction, the cancellation that adds water, is extracted with ethyl acetate, and merges after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, obtain faint yellow solid (2.45mg, 90%), i.e. formula 48-1 compound: LC-MS:265.2[M+H] +.
The preparation of step 2:N-propargyl-2-azido--3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 48-2 compound)
By formula 48-1 compound (68mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), propargylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (56mg, 73%), i.e. formula 48-2 compound: LC-MS:311.3[M+H] +.
The preparation of step 3:N-propargyl-2-amino-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 48 compounds)
Formula 48-2 compound (690mg, 2.52mmol) is dissolved in tetrahydrofuran (THF), adds triphen oxygen phosphorus (843mg, 3.03mmol), water (455mg, 25.3mmol), stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (653mg, 91%), i.e. formula 48 compounds: LC-MS:285.3[M+H] +.
The preparation of embodiment 49.N-cyclopropyl-2-methyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 49 compounds)
The preparation of step 1:2-methyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 49-1 compound)
By formula 36-1 compound (1.06mg, 4.56mmol) be dissolved in dry tetrahydrofuran (THF), be chilled to-78 degrees Celsius, drip LDA (3.4mL, 2M tetrahydrofuran solution 6.84mmol), finish reaction 1 hour, drip methyl iodide (777mg, 5.48mmol), after adding, reaction 2-4 hour.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water is extracted with ethyl acetate, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (776mg, 69%), i.e. formula 49-1 compound: LC-MS:247.3[M+H] +.
The preparation of step 2:N-cyclopropyl-2-methyl-3-((S)-2,6,7,8-tetrahydrochysene-1H-indeno [5,4-b] furans-8-yl) propionic acid amide (formula 49 compounds)
By formula 49-1 compound (61mg, 0.247mmol) be dissolved in dry methylene dichloride, add HATU (141mg, 0.371mmol), propargylamine (28mg, 0.492mmol), salt of wormwood (52mg, 0.371mmol), after adding, stirring at room temperature reaction is spent the night.After thin-layer chromatography detection reaction, the cancellation that adds water, separatory, water dichloromethane extraction, merge after organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, filtration is spin-dried for, column chromatography, obtains white solid (58mg, 82%), i.e. formula 49 compounds: LC-MS:286.4[M+H] +.
Embodiment 50 above-claimed cpd of the present invention is for melatonin (MT1-MT2) receptor agonist activity
Experimental technique please refer to document: Genomics.27 (2): 355 – 7, Endocrinology.139 (7): 3064 – 71.
By CHO/MT1 clone wink turning G α 16, after being activated, acceptor can cause the activation of G α 16 albumen, and then activate Phospholipase C (PLC) and produce IP3 and DAG, IP3 can with endoplasmic reticulum in cell and plastosome on IP3 receptors bind, thereby cause the release of cellular calcium.Therefore, the variation of mensuration cellular calcium can be used as the method that detects MT1 active state.Fluo-4/AM is that a kind of calcium fluorescent probe indicator is used for measuring calcium ion, as nonpolar fat-soluble compound, enters after cell under the effect of cell lipolytic enzyme, and AM group dissociates, and disengages Fluo-4; Because Fluo-4 is polar molecule, be difficult for by bimolecular lipid membrane, it can make Fluo-4 be retained in for a long time in cell.The fluorescence intensity that finally can be excited by measurement reflects the level that G albumen is activated.If the compound of screening can activate MT1 acceptor, can cause calcium current reaction.
By the CHO/MT1 cell kind that turns G α 16 wink in 96 orifice plates, overnight incubation.Suck the training liquid in kind of the hole that has cell, add freshly prepared dyestuff 40 μ l holes, constant-temperature incubation 40 minutes in 37 DEG C of incubators.With calcium damping fluid by drug dilution to be measured and mix.Dyestuff is exhausted and discarded, wash after one time with freshly prepared calcium damping fluid, change the calcium damping fluid of 50 μ l.With the detection of FlexStation II instrument, beginning in the 15th second adds 25 μ l to be dissolved with the calcium damping fluid of MT1 acceptor agonist to be detected by instrument automatically, finally reads 525nm place fluorescent value.50% exciting concentration (EC 50) value utilizes least square method to calculate by dosage-response curve.
Experimental result: the biological activity test of representative compound of the present invention the results are shown in Table 2.
Table 2: compound of the present invention is to melatonin (MT1-MT2) receptor agonist activity
The compounds of this invention is external as can be seen from Table 2 has stronger agonist activity for melatonin (MT1-MT2) acceptor, and majority of compounds external activity approaches or is better than contrasting medicine ramelteon, shows that the compounds of this invention has excellent activity.Especially compound 7, its external activity is better than ramelteon greatly.
Embodiment 51 the compounds of this invention normal rat internal metabolism experiments
Experimental technique:
4 of healthy SD rats, male, body weight 200-220g, gavage gives tested compound 2, compound 3, compound 41 and compound 44 simultaneously, and it is 5mg/kg that gavage gives dosage, and administration volume is 10ml/kg; Fasting 12h before test, freely drinks water.The unified feed of 2h after administration.Blood sampling time point and sample preparation: after administration 0.25,0.5,1.0,2.0,3.0,4.0,6.0,8.0 and 24h through rat eye rear vein beard extracting vein blood 0.3ml, put in heparinization test tube, the centrifugal 5min of 11000rpm, 20 DEG C of refrigerator and cooled of separated plasma ， Yu – are frozen.Use LC/MS method to measure the plasma concentration of each sampling spot.Experimental result is as following table 3.
Table 3: compound 2, compound 3, compound 41, compound 44 are for normal rat internal metabolism data sheet
The compounds of this invention 2,3,41 and 44 has good Pharmacokinetics in Rat parameter as can be seen from Table 3, especially compound 2,41,44, and longer Half-life in vivo and desirable drug disposition exposed amount are better than contrasting medicine greatly.Show that the compounds of this invention has obvious quasi-medicated property, be applicable to the disease that treatment or prevention are relevant to melatonin (MT1-MT2) acceptor, as insomnia and dysthymia disorders etc.
Embodiment 52 inhibition of compound 2 to hERG potassium channel
The HEK-293 cell of stably express hERG, at room temperature records hERG potassium channel current with full cell patch tongs technology.Tip resistance is that the glass microelectrode of 1-4M Ω left and right is connected to Axon200A patch clamp amplifier.Clamp down on voltage and data logging by clampex9.2 software through Axon DigiData1322A A/D converter by computer control, cell clamp, built in-80mV, brings out hERG potassium current (I hERG) the step voltage depolarize voltage that gives a 2s from-80mV to+20mV, then repolarization is to-40mV, continues get back to-80mV after 4s.Before and after administration, give this voltage step respectively and induce hERG potassium current.
Different pharmaceutical concentration is calculated with following formula the inhibition degree of hERG potassium current:
Inhibiting rate %=[1 – (I hERG-Drug/ I hERG-Control)] %
Wherein, inhibiting rate represents that medicine is to I hERGinhibition degree, I hERG-Drugand I hERG-Controlbe illustrated respectively in after dosing and dosing before I hERGamplitude.
The inhibition active testing that compound 2 carries out hERG potassium channel shows: compound 2 is very faint to the effect of hERG, and its activity of inhibition to hERG is IC 50>75uM, proves that the compounds of this invention has good security to cardiovascular systems.
Embodiment 53 compound 2 chmice acute toxicity tests
50 kunming mouses are chosen in the oral acute toxicity test of mouse, and male and female half and half are divided into 5 groups at random, and 10 every group, male and female half and half; With 0.5% Xylo-Mucine preparation compound 2 suspensions, be respectively 21.3,27.1,35.0,46.5,60mg/mL, press 0.5mL/20g body weight dosage gastric infusion, gavage that dosage is respectively 525.9,688.5,865.7,1537.5,2000mg/kg body weight, observe the toxicity symptom of animal, record death toll, calculate maximum tolerated dose and medium lethal dose, continue 1 week.
Conclusion: give after mouse gavaging compound 2, each treated animal is all without Novel presentation, and diet wish and cerebration are all right, do not occur dead; Its maximum tolerated dose and LD are described 50>2000mg/kg body weight.Show that the acute medication of compound 2 is safer.
The compounds of this invention has the active and excellent drug metabolism character of very strong inhibition and good security to melatonin (MT1-MT2) acceptor, be better than having at present medicine, can be used for the medicine of the diseases such as insomnia that preparation treatment melatonin (MT1-MT2) acceptor is relevant, anxiety, depression.
Embodiment 54 compound 2 chmice acute toxicity tests
This Preliminary Experiment has been studied pharmacokinetic property in rat body of compound 2 and Ramelteon and distribution characteristics in brain, liver, lung and spleen tissue.Rat oral gavage and intravenous injection give after tested compound, gather different time points blood plasma and tissue.Concentration with LC-MS/MS test-compound in blood plasma and tissue.
Test operation:
24 of healthy SD rats, male, body weight 200-220g, is divided into 2 groups, and 12 every group, distribution gavage gives tested compound, and concrete arrangement sees the following form 4:
Table 4
Fasting 12h before test, freely drinks water.The unified feed of 2h after administration.
After gastric infusion, put to death rat at setting-up time point, three of each time points, gather lung, spleen, brain and hepatic tissue, and tissue rushes quiet with ice physiological saline, post 20 DEG C of refrigerator and cooled of note ， – and freeze after blotting.
Table 5 rat oral gavage gives the concentration (ng/g) at each tissue after 20mg/kg compound 2
Table 6 rat oral gavage gives the concentration (ng/g) at each tissue after 20mg/kg Ramelteon
After rat difference gavage 20mg/kg compound 2 and Ramelteon, in each tissue of investigating, compound concentration is in table 5 and table 6.
After rat oral gavage 20mg/kg compound 2, in liver, concentration is the highest, is secondly brain, and in spleen and lung tissue, relative concentration is lower.Compound 2 concentration 0.5h after administration in each tissue reaches peak, eliminates comparatively fast, and after administration 4h, concentration is peak concentration 1.5%～7.7%.
Under same dose, the concentration of compound 2 in rats'liver, brain, spleen and lung group is respectively 3.7～26.8 times, 20.1～47.2 times, 15.2～35.6 times and 14.4～28.8 times of Ramelteon concentration.The exposed amount of compound 2 in each tissue is all higher than the concentration of Ramelteon.Compound 2 acts on sleep, it is highly important that and need to pass through hemato encephalic barrier, enters brain, performance drug effect.Can find out from the result of tissue distribution, the distribution of our compound 2 in brain is better than control sample ramelteon greatly.

Claims (17)

1. class melatonin (MT1-MT2) receptor stimulant, it is following general formula (I) compound or its optical isomer:
Wherein:
N is selected from: 1-5;
A is selected from: CH 2, oxygen, or NH;
be selected from: (two key) or-(singly-bound);
D is selected from: CH 2or oxygen;
B is selected from:
Wherein R is selected from: hydrogen, C 1-C 6straight chain saturated alkyl or C 3-C 6saturated branched-chain alkyl or C 3-C 6cycloalkyl or C 3-C 6unsaturated straight or branched alkyl; Described alkyl is unsubstituted or is replaced by one to three group that is independently selected from lower group: halogen, OH, NH 2, or CN;
R 1be selected from hydrogen or fluorine;
R 2be selected from hydrogen, hydroxyl, sulfydryl, amino, halogen or C 1-C 6straight or branched alkyl;
R 3be selected from C 1-C 6straight chained alkyl or C 3-C 6branched-chain alkyl; Described alkyl is unsubstituted or is replaced by one to three group that is independently selected from lower group: halogen, OH, NH 2, or CN.
2. melatonin as claimed in claim 1 (MT1-MT2) receptor stimulant, it is characterized in that, general formula (I) contains 1 or 2 chiral carbon atoms, and general formula (I) compound comprises single enantiomer, non-enantiomer mixture, racemic modification and single diastereomer.
3. melatonin as claimed in claim 1 (MT1-MT2) receptor stimulant, it is characterized in that, described compound is following formula 1 compound, formula 2 compounds, formula 3 compounds, formula 4 compounds, formula 5 compounds, formula 6 compounds, formula 7 compounds, formula 8 compounds, formula 9 compounds, formula 10 compounds, formula 11 compounds, formula 12 compounds, formula 13 compounds, formula 14 compounds, formula 15 compounds, formula 16 compounds, formula 17 compounds, formula 18 compounds, , formula 19 compounds, formula 20 compounds, formula 21 compounds, formula 22 compounds, formula 23 compounds, formula 24 compounds, formula 25 compounds, formula 26 compounds, formula 27 compounds, formula 28 compounds, formula 29 compounds, formula 30 compounds, formula 31 compounds, formula 32 compounds, formula 33 compounds, formula 34 compounds, formula 35 compounds, formula 36 compounds, formula 37 compounds, formula 38 compounds, formula 39 compounds, formula 40 compounds, formula 41 compounds, formula 42 compounds, formula 43 compounds, formula 44 compounds, formula 45 compounds, formula 46 compounds, formula 47 compounds, formula 48 compounds, formula 49 compounds:
4. a preparation method for melatonin (MT1-MT2) receptor stimulant as claimed in claim 1,
Its reaction formula is as follows:
The method comprises the steps: at suitable temperature, adds organic solvent dissolution formula A-1 compound, formula A-2 compound, coupling reagent, alkali, and reaction obtains formula IA compound;
Described organic solvent is selected non-protonic solvent, described coupling reagent is N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide, N, N'-DIC, 4, 5-dicyano imidazole, N, N'-carbonyl dimidazoles, 1-hydroxy benzo triazole, 1-hydroxyl-7-azo benzotriazole, O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, or 6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester, described alkali is organic bases or mineral alkali, the molar ratio of formula A-2 compound and formula A-1 compound is 1.1-2, the molar ratio of coupling reagent and formula A-1 compound is 1.1-2, alkali and formula A-1 compound are thrown mol ratio 1.0-10.0, temperature of reaction is 0 DEG C-100 DEG C, reaction times is 5-48 hour.
5. a preparation method for melatonin (MT1-MT2) receptor stimulant as claimed in claim 1,
Its reaction formula is as follows:
The method comprises the steps:
L) reduction of formula B-1 compound obtains formula B-2 compound: reductive agent is dissolved in organic solvent, slowly adds the organic solvent solution of formula B-1 compound, obtain formula B-2 compound after reaction; Described organic solvent is selected non-protonic solvent; Described reductive agent is sodium borohydride-lewis acid system, sodium borohydride-organic acid acid system, lithium aluminum hydride, diisobutyl aluminium hydride, red aluminium, or K-selectride; Temperature of reaction is 0 DEG C-60 DEG C; Reaction times is 0.5-24 hour;
2) formula B-2 compound transforms and obtains formula B-3 compound: formula B-2 compound is dissolved in organic solvent, adds alkali, drip methylsulfonyl chloride (Methanesulfonyl chloride), room temperature reaction obtains formula B-3 compound; Described organic solvent is selected non-protonic solvent; Described alkali is mineral alkali or organic bases; The molar ratio of alkali and formula B-2 compound is 1.0-20.0; Temperature of reaction is 0 DEG C-60 DEG C; Reaction times is 1-48 hour;
3) formula B-3 compound transforms and obtains formula B-4 compound: formula B-3 compound is dissolved in organic solvent, adds cyanide salt, reaction obtains formula B-4 compound; Described organic solvent is selected non-protonic solvent; Described cyanide salt and formula B-3 compound molar ratio are 1.0-20.0; Temperature of reaction is 0 DEG C-160 DEG C; Reaction times is 1-24 hour;
4) formula B-4 compound transforms and obtains formula B-5 compound: formula B-4 compound is dissolved in organic solvent, adds alkali and hydrogen peroxide, reaction obtains formula B-5 compound; Described organic solvent is selected protic or non-protonic solvent; Alkali is mineral alkali or organic bases; The molar ratio of alkali and formula B-4 compound is 1.0-10.0; The molar ratio of hydrogen peroxide and formula B-4 compound is 1.0-10.0; Temperature of reaction is 0 DEG C-100 DEG C; Reaction times is 1-24 hour.
6. a preparation method for melatonin (MT1-MT2) receptor stimulant as claimed in claim 1,
Its reaction formula is as follows:
The method comprises the steps:
1) formula B-4 compound transforms and obtains formula C-1 compound: formula B-4 compound is dissolved in organic solvent, adds alkali, reaction obtains formula C-1 compound; Described organic solvent is selected protic or non-protonic solvent; Described alkali is mineral alkali; The molar ratio of described alkali and formula B-4 compound is 1.0-10.0; Temperature of reaction is 0 DEG C-160 DEG C; Reaction times is 1-24 hour;
2) formula C-1 compound transforms and obtains formula IC compound: at suitable temperature, add organic solvent dissolution formula C-1 compound, aminated compounds, coupling reagent, alkali, reaction obtains formula IC compound, described organic solvent is selected non-protonic solvent, described aminated compounds is the simple amine of C2-C6, described coupling reagent is N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide, N, N'-DIC, 4, 5-dicyano imidazole, N, N'-carbonyl dimidazoles, 1-hydroxy benzo triazole, 1-hydroxyl-7-azo benzotriazole, O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, 6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester, described alkali is organic bases or mineral alkali, the molar ratio of described aminated compounds and formula C-1 compound is 1.1-2, the molar ratio of coupling reagent and formula C-1 compound is 1.1-2, alkali and formula C-1 compound molar ratio 1.0-10.0, temperature of reaction is 0 DEG C-100 DEG C, reaction times is 5-48 hour.
7. a preparation method for melatonin (MT1-MT2) receptor stimulant as claimed in claim 1,
Its reaction formula is as follows:
The method comprises the steps:
1) formula C-1 compound transforms and obtains formula D-1 compound: formula C-1 compound is dissolved in organic solvent, adds acid, reaction obtains formula D-1 compound: described organic solvent is selected protic or non-protonic solvent; The molar ratio of described acid and formula C-1 compound is 1.0-10.0; Temperature of reaction is 0 DEG C-160 DEG C; Reaction times is 1-24 hour;
2) formula D-1 compound transforms and obtains formula ID compound: at suitable temperature, add organic solvent dissolution formula D-1 compound, methylamine, reaction obtains formula ID compound; Described organic solvent is selected non-protonic solvent; The molar ratio of methylamine and formula D-1 compound is 1.1-2; Temperature of reaction is 0 DEG C-100 DEG C; Reaction times is 5-48 hour.
8. a preparation method for melatonin (MT1-MT2) receptor stimulant as claimed in claim 1,
Its reaction formula is as follows:
The method comprises the steps:
1) formula E-1 compound transforms and obtains formula E-2 compound: formula E-1 compound is dissolved in organic solvent, adds Methyl benzenesulfonyl methyl isonitrile and alkali, reaction obtains formula E-2 compound; Described organic solvent is selected protic or non-protonic solvent; Described alkali is organic bases or mineral alkali; The molar ratio of alkali and formula E-1 compound is 1.0-10.0; Temperature of reaction is-10 DEG C-160 DEG C; Reaction times is 1-48 hour;
2) reduction of formula E-2 compound obtains formula E-3 compound: reductive agent is dissolved in organic solvent, slowly adds the organic solvent solution of formula E-2 compound, obtain formula E-3 compound after reaction; Described organic solvent is selected non-protonic solvent; Described reductive agent is selected from diisobutyl aluminium hydride, red aluminium, or K-selectride; Temperature of reaction is-100 DEG C-60 DEG C; Reaction times is 0.5-24 hour;
3) formula E-3 compound reduction obtains formula E-4 compound: ethyl bromide difluoride is added dropwise in the organic solvent that contains activated zinc powder, obtains formula E-4 compound after adding afterwards the reaction of formula E-3 compound; Described organic solvent is selected non-protonic solvent; Temperature of reaction is 0 DEG C-100 DEG C; Reaction times is 0.5-24 hour;
4) reduction of formula E-4 compound obtains formula E-5 compound: formula E-4 compound is dissolved in organic solvent, adds dithiocarbonic anhydride and alkali, react after 0.5-5 hour, add methyl iodide, obtain intermediate; Described organic solvent is selected non-protonic solvent; Temperature of reaction is 0 DEG C-100 DEG C; Reaction times is 0.5-24 hour;
Above-mentioned intermediate is dissolved in organic solvent, adds peroxy tert-butyl alcohol and triphenyl phosphorus H-H reaction to obtain formula E-5 compound; Described organic solvent is selected non-protonic solvent; Temperature of reaction is 0 DEG C-100 DEG C; Reaction times is 0.5-24 hour;
5) reduction of formula E-5 compound obtains formula E-6 compound: formula E-5 compound is dissolved in organic solvent and water mixed solvent, adds alkali, reaction obtains formula E-6 compound; Described organic solvent is selected protic or non-protonic solvent; Described alkali is mineral alkali; The molar ratio of alkali and formula E-5 compound is 0.01-10.0; Temperature of reaction is 0 DEG C-160 DEG C; Reaction times is 1-24 hour;
6) formula E-6 compound transforms and obtains formula IE compound: at suitable temperature, add organic solvent dissolution formula E-6 compound, aminated compounds, coupling reagent, alkali, reaction obtains formula IE compound, described organic solvent is selected non-protonic solvent, described aminated compounds is the simple amine of C2-C6, described coupling reagent is N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide, N, N'-DIC, 4, 5-dicyano imidazole, N, N'-carbonyl dimidazoles, 1-hydroxy benzo triazole, 1-hydroxyl-7-azo benzotriazole, O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, 6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester, described alkali is organic bases or mineral alkali, the molar ratio of described aminated compounds and formula E-6 compound is 1.1-2, the molar ratio of coupling reagent and formula E-6 compound is 1.1-2, alkali and formula E-6 compound molar ratio 1.0-10.0, temperature of reaction is 0 DEG C-100 DEG C, reaction times is 5-48 hour.
9. a preparation method for melatonin (MT1-MT2) receptor stimulant as claimed in claim 1,
Its reaction formula is as follows:
The method comprises the steps:
L) reduction of formula F-1 compound obtains formula F-2 compound: reductive agent is dissolved in organic solvent, slowly adds the organic solvent solution of formula F-1 compound, obtain formula F-2 compound after reaction; Described organic solvent is selected non-protonic solvent; Described reductive agent is sodium borohydride, sodium borohydride-lewis acid system, sodium borohydride-organic acid acid system, lithium aluminum hydride, diisobutyl aluminium hydride, red aluminium, or K-selectride; Temperature of reaction is 0 DEG C-60 DEG C; Reaction times is 0.5-24 hour;
2) formula F-2 compound transforms and obtains formula F-3 compound: formula F-2 compound is dissolved in organic solvent, adds alkali and ethyl bromoacetate, reaction obtains formula F-3 compound; Described organic solvent is selected protic or non-protonic solvent; Described alkali is mineral alkali; The molar ratio of alkali and formula F-2 compound is 0.1-10.0; The molar ratio of ethyl bromoacetate and formula F-2 compound is 1-10.0; Temperature of reaction is 0 DEG C-160 DEG C; Reaction times is 1-24 hour;
3) formula F-3 compound transforms and obtains formula F-4 compound: formula F-3 compound is dissolved in organic solvent and water mixed solvent, adds alkali, reaction obtains formula F-4 compound; Described organic solvent is selected protic or non-protonic solvent; Described alkali is mineral alkali; The molar ratio of alkali and formula F-3 compound is 0.01-10.0; Temperature of reaction is 0 DEG C-160 DEG C; Reaction times is 1-24 hour;
4) formula F-4 compound transforms and obtains formula IF compound: at suitable temperature, add organic solvent dissolution formula F-4 compound, aminated compounds, coupling reagent, alkali, reaction obtains formula IF compound, described organic solvent is selected non-protonic solvent, described aminated compounds is the simple amine of C2-C6, described coupling reagent is N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide, N, N'-DIC, 4, 5-dicyano imidazole, N, N'-carbonyl dimidazoles, 1-hydroxy benzo triazole, 1-hydroxyl-7-azo benzotriazole, O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, 6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester, described alkali is organic bases or mineral alkali, the molar ratio of described aminated compounds and formula F-4 compound is 1.1-2, the molar ratio of coupling reagent and formula F-4 compound is 1.1-2, alkali and formula F-4 compound molar ratio 1.0-10.0, temperature of reaction is 0 DEG C-100 DEG C, reaction times is 5-48 hour.
10. a preparation method for melatonin (MT1-MT2) receptor stimulant as claimed in claim 1,
Its reaction formula is as follows:
The method comprises the steps:
L) formula C-1 compound transforms and obtains formula G-1 compound: formula C-1 compound is dissolved in organic solvent, adds brominated reagent, reaction obtains formula G-1 compound; Described organic solvent is selected protic or non-protonic solvent; Described brominated reagent is phosphorus tribromide or red phosphorus-bromine; The molar ratio of brominated reagent and formula C-1 compound is 1-50.0; Temperature of reaction is-50 DEG C-160 DEG C; Reaction times is 1-72 hour;
2) formula G-1 compound transforms and obtains formula G-2 compound: formula G-1 compound is dissolved in organic solvent and water mixed solvent, adds alkali, reaction obtains formula G-2 compound; Described organic solvent is selected protic or non-protonic solvent; Alkali is mineral alkali; The molar ratio of alkali and formula G-1 compound is 0.01-10.0; Temperature of reaction is-50 DEG C-160 DEG C; Reaction times is 1-48 hour;
3) formula G-2 compound transforms and obtains formula IG compound: at suitable temperature, add organic solvent dissolution formula G-2 compound, aminated compounds, coupling reagent, alkali, reaction obtains formula IG compound, described organic solvent is selected non-protonic solvent, described aminated compounds is the simple amine of C2-C6, described coupling reagent is N-(3-dimethylamino-propyl)-N'-ethyl-carbodiimide hydrochloride, dicyclohexylcarbodiimide, N, N'-DIC, 4, 5-dicyano imidazole, N, N'-carbonyl dimidazoles, 1-hydroxy benzo triazole, 1-hydroxyl-7-azo benzotriazole, O-(7-nitrogen benzotriazole)-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, O-benzotriazole-N, N, N', N'-tetramethyl-urea Tetrafluoroboric acid ester, benzotriazole-N, N, N', N'-tetramethyl-urea phosphofluoric acid ester, 6-Chloro-Benzotriazole-1, 1, 3, 3-tetramethyl-urea phosphofluoric acid ester, described alkali is organic bases or mineral alkali, the molar ratio of described aminated compounds and formula G-2 compound is 1.1-2, the molar ratio of coupling reagent and formula G-2 compound is 1.1-2, alkali and formula G-2 compound molar ratio 1.0-10.0, temperature of reaction is 0 DEG C-100 DEG C, reaction times is 5-48 hour.
11. 1 kinds of preparation methods of melatonin (MT1-MT2) receptor stimulant as claimed in claim 1, its reaction formula is as follows:
The method comprises the steps: formula IG compound to transform and obtain formula IH compound: formula IG compound is dissolved in organic solvent, adds fluoro reagent, reaction obtains formula IH compound; Described organic solvent is selected protic or non-protonic solvent; The molar ratio of fluoro reagent and formula IG compound is 1-50.0; Temperature of reaction is-50-100 DEG C; Reaction times is 1-72 hour.
12. 1 kinds of preparation methods of melatonin (MT1-MT2) receptor stimulant as claimed in claim 1, its reaction formula is as follows:
The method comprises the steps:
1) formula G-1 compound transforms and obtains formula I-1 compound: formula G-1 compound is dissolved in solvent, adds sulfo-reagent, at suitable temperature, reaction obtains formula I-1 compound; Described solvent is selected from water, DMF, a kind of or any multiple mixture in DMSO; Described sulfo-reagent is Sodium sulfhydrate; The molar ratio of sulfo-reagent and formula G-1 compound is 1-50.0; Temperature of reaction is-50-100 DEG C; Reaction times is 1-72 hour;
2) formula I-1 compound transforms and obtains formula II compound: operation is with described in claim 4, formula A-1 compound being transformed to the method that obtains formula IA compound.
13. 1 kinds of preparation methods of melatonin (MT1-MT2) receptor stimulant as claimed in claim 1, its reaction formula is as follows:
The method comprises the steps:
1) formula G-1 compound transforms and obtains formula J-1 compound: at suitable temperature, formula G-1 compound is dissolved in solvent, adds nitrine reagent, reaction obtains formula J-1 compound; Described solvent is selected DMF, a kind of or any multiple mixture in DMSO; Nitrine reagent is elected sodiumazide as; The molar ratio of nitrine reagent and formula J-1 compound is 1-50.0; Temperature of reaction is-50-100 DEG C; Reaction times is 1-72 hour;
2) formula J-1 compound transforms and obtains formula J-2 compound: operation is with described in claim 4, formula A-1 compound being transformed to the method that obtains formula IA compound;
3) formula J-2 compound transforms and obtains formula IJ compound: formula J-2 compound is dissolved in solvent, and at suitable temperature, reduction obtains formula IJ compound; Described solvent is selected tetrahydrofuran (THF), methylene dichloride, a kind of or any multiple mixture in toluene; Also original reagent is triphenyl phosphorus/aqueous systems, or hydrogen/palladium carbon system; Also the molar ratio of original reagent and formula J-2 compound is 1-50.0; Temperature of reaction is-50-100 DEG C; Reaction times is 1-72 hour.
14. 1 kinds of preparation methods of melatonin (MT1-MT2) receptor stimulant as claimed in claim 1, its reaction formula is as follows:
The method comprises the steps:
1) formula C-1 compound transforms and obtains formula K-1 compound: formula C-1 compound is dissolved in organic solvent, at suitable temperature, adds alkylating reagent, reaction obtains formula K-1 compound; Described organic solvent is selected tetrahydrofuran (THF), toluene, normal hexane, a kind of or any multiple mixture in methylene dichloride; Alkylating reagent is methyl iodide, monobromethane, n-propyl bromide, or methyl-sulfate; The molar ratio of alkylating reagent and formula G-1 compound is 1-50.0; Temperature of reaction is-80-100 DEG C; Reaction times is 1-72 hour;
2) formula K-1 compound transforms and obtains formula IK compound: operation is with described in claim 4, formula A-1 compound being transformed to the method that obtains formula IA compound.
15. 1 kinds of preparation methods of melatonin (MT1-MT2) receptor stimulant as claimed in claim 1, its reaction formula is as follows:
The method comprises the steps:
1) formula B-1 compound transforms and obtains formula L-1 compound: formula L-1 compound is dissolved in organic solvent, adds oxidising agent, at suitable temperature, reaction obtains formula L-1 compound; Described organic solvent is selected tetrahydrofuran (THF), toluene, normal hexane, a kind of or any multiple mixture in methylene dichloride; Oxidising agent is Manganse Dioxide, oxalyl chloride/methyl-sulphoxide/triethylamine system, Dess-Martin oxygenant, PCC, PDC, methyl-sulphoxide-sulphur trioxide complex compound or two oxidation of methylpyridine chromium; The molar ratio of oxidising agent and formula L-1 compound is 1-50.0; Temperature of reaction is-80-100 DEG C; Reaction times is 1-72 hour;
2) formula L-1 compound transforms and obtains formula L-2 compound: formula L-1 compound is dissolved in organic solvent, adds chiral ligand, cyanating reagent, triphen oxygen phosphorus, at suitable temperature, after reaction for some time, pH=1～2 are adjusted in acidifying, and at suitable temperature, reaction obtains formula L-2 compound; Described organic solvent is selected tetrahydrofuran (THF), toluene, normal hexane, a kind of or any multiple mixture in methylene dichloride; Chiral ligand is (S)-bis-(3,5-dimethyl is stupid) (pyrrolidin-2-yl) methyl alcohol; Cyanating reagent is trimethyl silicane nitrile or potassium cyanide; The molar ratio of chiral ligand and formula L-1 compound is 0.01-50.0; The molar ratio of cyanating reagent and formula L-1 compound is 1-50.0; The molar ratio of triphen oxygen phosphorus and formula L-1 compound is 0.01-50.0; Described acidifying with acid be concentrated hydrochloric acid, methanesulfonic, the vitriol oil or phosphoric acid; Temperature of reaction is-80-100 DEG C; Reaction times is 1-72 hour;
3) formula L-2 compound transforms and obtains formula L-3 compound: formula L-2 compound is dissolved in organic solvent, adds acid, at suitable temperature, reaction obtains formula L-3 compound; Described organic solvent is selected a kind of or its mixture in methyl alcohol, ethanol; Described acid is concentrated hydrochloric acid, methanesulfonic, the vitriol oil, phosphoric acid; Acid with solvent the volume ratio that feeds intake be 0.01 – 1; Temperature of reaction is-80-100 DEG C; Reaction times is 1-72 hour;
4) formula L-3 compound transforms and obtains formula L-4 compound: formula L-3 compound is dissolved in organic solvent, adds alkali, at suitable temperature, reaction obtains formula L-4 compound; Described organic solvent is selected a kind of or its mixture in methyl alcohol, ethanol, tetrahydrofuran (THF); Alkali is sodium hydroxide, potassium hydroxide, lithium hydroxide; The molar ratio of alkali and formula L-3 compound is 1 – 50; Temperature of reaction is-80-100 DEG C; Reaction times is 1-72 hour.
5) formula L-4 compound transforms and obtains formula IL compound: operation is with described in claim 4, formula A-1 compound being transformed to the method that obtains formula IA compound.
16. 1 kinds of preparation methods of melatonin (MT1-MT2) receptor stimulant as claimed in claim 1, its reaction formula is as follows:
The method comprises the steps:
1) formula L-1 compound is transformed and obtains formula M-1 compound: operation is with described in claim 15, formula L-1 compound being transformed to the method that obtains formula L-2 compound;
2) formula M-1 compound is transformed and obtains formula M-2 compound: operation is with described in claim 15, formula L-2 compound being transformed to the method that obtains formula L-3 compound;
3) formula M-2 compound transforms and obtains formula M-3 compound: operation is with described in claim 15, formula L-3 compound being transformed to the method that obtains formula L-4 compound;
4) formula M-3 compound transforms and obtains formula IM compound: operation is with described in claim 4, formula A-1 compound being transformed to the method that obtains formula IA compound.
Application in the medicine of the disease that 17. melatonin as claimed in claim 1 (MT1-MT2) receptor stimulants are relevant to melatonin MT1-MT2 acceptor in preparation treatment.
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