CN101265221A - Modafinil fluorine-containing analogue and synthesizing method thereof - Google Patents

Abstract

The invention relates to modafinil fluorine-containing analog and a synthesis method thereof, belongs to the technology field of medical chemistry, and aims to provide the modafinil fluorine-containing analog with higher activity and the synthesis method thereof which are found through leading a difluoro methylene fragment into the molecular structure of modafinil medicine. The method has the technical key points that Ethyl bromodifluoroacetate is ammonolyzed to obtain bromine difluoro acetamide which reacts with diphenyl methyl mercaptan through nucleophilic substitution to obtain diphenyl benzhydrylamine hydrosulphonyl difluoro acetamide; finally, the diphenyl benzhydrylamine hydrosulphonyl difluoro acetamide is oxidized to obtain modafinil difluoro methylene-containing analog. The modafinil fluorine-containing analog has the characteristics that the method is simple, the technological route is advanced, the process conditions are reasonable, the raw material has low price and is easy to get, the operation is simple and safe, the yield rate is high, the cost is low without pollution, etc. In addition, the industrialized production is easy to realize. Excitability test performed on mice shows that the modafinil fluorine-containing analog has nervous excitability effect to the mice, the excitability effect is stronger than the modafinil, and the time of the excitability effect is longer.

Description

Modafinil fluorine-containing analogue and synthetic method thereof

Technical field

The present invention relates to a kind of modafinil fluorine-containing analogue and synthetic method thereof, belong to the medical chemistry technical field.

Background technology

Modafinil (modafinil) is a kind of novel central nervous excitation agent of non-amphetamine.

Chemical name: 2-diphenyl-methyl-sulfinyl ethanamide

Molecular structural formula:

CAS number: [68693-11-8]

Molecular formula: C ₁₅H ₁₅NO ₂S

Molecular weight: 273.36

1993, modafinil was at first found by the L.Lafon laboratory, went on the market in France with the trade(brand)name of modiodal first in 1994, after this successively in Britain, Japan, Italy, Mexico's listing.FDA approval in 1998 is used for the treatment of narcolepsy, and trade(brand)name is provigil, is first medicine that is used for the treatment of lethargy.Modafinil is as the drowsiness and ictal drowsiness patient's of treatment medicine, and it is efficient to be approximately 70%, has characteristics such as safety, tolerability is fabulous, side effect is very little, does not particularly disturb patient testing laboratory parameter and liver function index.Modafinil can make drowsiness patient revive in school, family, society and Job, and near the normal people.In view of short awake effect of modafinil and less side effect, caused various countries military medicine researchist, particularly aviation military medicine worker's great attention.French Air Force has successfully used antifatigue and the central nervous system stimulants of modafinil as the pilot personnel in the Gulf War, and this medicine of equipment guarantees that alertness was arranged in 48 hours in pilot's survival aids.

In found more than 100 years time, fluorochemicals has obtained in various fields such as industry, agricultural, medicine using widely at fluorine element, and application and research that particularly low fluoro has physiologically active compound become a very popular topic.

Fluorine-containing pharmaceutical chemical systematic study to biologically active starts from the fifties in last century.1954, Fried was in the process of research cortisone (cortisone) derivative, and the cortisone derivative of finding 9 fluorine replacements is as glucocorticosteroid, and its activity is higher 10～12 times than non-fluorine replacement.This is unexpected finds to have promoted that at that time to the research of this compounds fluorine substitutive derivative, the result has caused many discoveries with fluorine-containing medicine of using value.Yet what have more breakthrough meaning is that to have synthesized the end of the fifties in last century with 5 FU 5 fluorouracil (5-FU) be the nucleic acid antagonist (Nucleic AcidAntagonist) of representative.Chemists recognize gradually from that time, optionally introducing fluorine atom in organic molecule can make its physiologically active that beyond thought variation takes place, this fluorinated organic compound research for biologically active is laid a good foundation, and has promoted the development of this respect work greatly.Because the lipotropy (lipophilicity) of compound increases behind the introducing fluorine atom, thereby fluorochemicals the penetration power to film, tissue etc. is strong in vivo, improved absorption and the transfer rate of fluorochemicals in organism, some physiological actions of inside of human body have been changed, so many fluorine-containing medicines have characteristics such as consumption is few, toxicity is low, drug effect is high, the antimetabolic ability is strong on performance, thereby make it use more prevalent at field of medicaments.The fluorine-containing medicines of having developed so far is very many, since the fluoro steroid hormone fifties in last century, to nervus centralis medicine haloperidol (haloperidol), to adrenocortical hormone medicine Tr (triamacinalone), fluoroquinolone antibacterial agent Ofloxacine USP 23 (Ofloxacin) etc.

Summary of the invention

The object of the present invention is to provide a kind of difluoro methylene segment can being incorporated in the modafinil drug molecular structure, in the hope of finding active higher modafinil fluorine-containing analogue and synthetic method thereof.

The molecular structural formula of modafinil fluorine-containing analogue of the present invention is as follows:

The synthetic method of modafinil fluorine-containing analogue of the present invention may further comprise the steps:

1) the Bromodifluoroacetic acid ethyl ester is mixed with ether and fully after the dissolving, be cooled to about 0 ℃ at ice-water bath, stir and feed the exsiccant ammonia down, react to revolve after 8-9 hour and steam except that desolvating, the sherwood oil recrystallization obtains bromine two monofluoroacetamides;

2) two beneze methane thiols are mixed with dimethyl sulfoxide (DMSO) and fully after the dissolving, stir and add NaH down, exothermic heat of reaction, after temperature is reduced to about 22 ℃, slowly add bromine two monofluoroacetamides, after stirring reaction 10-14 hour, in reaction solution, add ammonium chloride saturated aqueous solution and regulate PH ≈ 7.0, through extraction, washing organic phase, drying, revolve to steam to remove and obtain hexichol first sulfydryl two monofluoroacetamides after desolvating;

3) hexichol first sulfydryl two monofluoroacetamides are mixed with methylene dichloride, stir down and slowly splash into hydrogen peroxide, after airtight stirring 9-10 hour, steaming desolventizes, and the crude product that obtains is removed impurity with column chromatography, revolves to steam to remove to desolvate again, and promptly gets modafinil fluorine-containing analogue.

Its technique effect is: the synthetic method of modafinil fluorine-containing analogue of the present invention, Bromodifluoroacetic acid ethyl ester ammonia is separated bromine two monofluoroacetamides that obtain, carry out nucleophilic substitution with two beneze methane thiols again and obtain hexichol first sulfydryl two monofluoroacetamides, at last the two monofluoroacetamide oxidations of hexichol first sulfydryl are obtained the analogue that modafinil contains difluoro methylene, it is simple to have method, the operational path advanced person, processing condition are reasonable, raw material is cheap and easy to get, safety simple to operate, the yield height, cost is low, characteristics such as pollution-free are easy to carry out suitability for industrialized production.

Adopt the modafinil fluorine-containing analogue that synthetic method of the present invention obtained, through excitability test to mouse, show that this modafinil fluorine-containing analogue has the central nervous excitation effect to mouse, its excitability action is stronger than modafinil, and the time of excitability action is longer.

Modafinil fluorine-containing analogue is to the influence of mouse autonomic activities:

Laboratory animal is divided into 5 groups at random, 10 every group, be respectively 1%SB control group, modafinil control group, benzhydrylsulfinyl base two monofluoroacetamide low dosage experimental group, middle dosage experiments group, high dosage experimental group, and the numbering mark.

Benzhydrylsulfinyl base two monofluoroacetamides (40mg/kg, 80mg/kg, the 160mg/kg) suspensions (0.4ml) of using modafinil (120mg/kg) suspension (0.4ml) that 1%SB solution (0.4ml), 1%SB make and 1%SB to make are respectively given mouse stomach.

Every mouse provides enough food in experiment night the day before yesterday, tests more than 12 hours under dark, comfortable quiet environment, and laboratory temperature remains on about 22 ℃, relative humidity 50～70%.Before mouse stomach and behind the filling stomach 30,60,90,120min and 24h respectively get a container of putting into tonotransducer, detect its mobility 2min.Because the container of tonotransducer is to be connected with inductor block by a line, when mouse was movable, changing will appear in the tension force of line, demonstrates the tension variation curve by Medlab bio signal acquisition processing system in computer monitor, and record is preserved.The mouse activity is frequent more, and the change frequency of curve is fast more; Mobility is big more, and the wave amplitude of curve is big more.Thereby can reflect the autonomic activities degree of mouse.For ease of statistical procedures, only calculate the movable number of times of fluctuating range, and obtain every group mean number and standard deviation and compare greater than 0.4g.The results are shown in following table:

Group	Before the administration	30min after the administration	60min after the administration	90min after the administration	120min after the administration	24h after the administration
							The 1%SB control group	23.2± 3.8	21.2± 3.2	10.2± 3.1	8.5± 3.1	7.9± 3.4	8.7± 3.4
The modafinil control group	22.9± 4.8	31.1± 8.5	31.5± 11.5	37.8± 14.4	35.3± 14.2	9.4± 4.2
							The low dosage experimental group	23.1± 3.6	26.3± 4.6	35.7± 9.1	36.8± 9.6	38.6± 9.8	24.3 ±5.6
Middle dosage experiments group	22.2± 6.4	23.5± 5.4	42.5± 10.2	43.0± 10.9	40.9± 12.9	26.7 ±7.1
							The high dosage experimental group	23.5± 4.3	44.9± 9.4	50.0± 10.9	52.3± 9.9	51.8± 8.9	27.2 ±4.5

Figure of description

Fig. 1 is bromine two monofluoroacetamide nuclear-magnetism fluorine collection of illustrative plates;

Fig. 2 is hexichol first sulfydryl two monofluoroacetamide nuclear-magnetism hydrogen collection of illustrative plates;

Fig. 3 is the similar nuclear-magnetism hydrogen of a modafinil fluorine-containing collection of illustrative plates.

Embodiment

1, the preparation of bromine two monofluoroacetamides

(20.3g 100mmol), ether (14mL), fully after the dissolving, is cooled to about 0 ℃ at ice-water bath, stirs and feeds the exsiccant ammonia down to add the Bromodifluoroacetic acid ethyl ester in the 50mL there-necked flask successively.With gas-chromatography monitoring reaction progress, react to revolve after 8 hours to steam to remove and desolvate, the sherwood oil recrystallization obtains white solid 12.75g.Compose through the nuclear-magnetism fluorine: ¹⁹F NMR (CDCl ₃470.5MHz) δ :-62.23 (2F, s ,-CBrF ₂) (seeing accompanying drawing 1) and high performance liquid phase (HPLC) confirm as bromine two monofluoroacetamides, yield: 73.3%, fusing point: 86.9～87.4 ℃, purity: 99.7%.

2, the preparation of hexichol first sulfydryl two monofluoroacetamides

In the 50mL there-necked flask, add two beneze methane thiol (2.0g successively, 10mmol), dimethyl sulfoxide (DMSO) (10mL), fully after the dissolving, stir and add NaH (50% down, 0.53g, 11mmol), exothermic heat of reaction, stir after 1 hour, temperature is reduced to (air-conditioning regulate under) room temperature (about 22 ℃), slowly adds bromine two monofluoroacetamide (1.74g, 10mmol), add under the room temperature of back and stir, analyse a plate monitoring reaction progress, finish after reaction is spent the night with silica gel thin-layer, in reaction solution, add ammonium chloride saturated aqueous solution and regulate PH ≈ 7.0, with methyl tertiary butyl ether (50mL * 3) extraction, distilled water (80mL * 3) washing organic phase is used saturated aqueous common salt (50mL) washing organic phase at last, anhydrous magnesium sulfate drying, revolve steam to remove and obtain faint yellow solid 2.1g after desolvating, with sherwood oil (PE): ethyl acetate (EA) (V/V)=10: 1 mixing solutions recrystallization obtains white solid (5) 1.7g, through nucleus magnetic hydrogen spectrum: ¹H NMR (CDCl ₃500MHz) δ: 5.68 (1H, s ,-NH ₂), 6.05 (1H, s ,-NH ₂), 5.77 (1H, s ,-CH-S-), 7.25～7.42 (10H, m, (C ₆H ₅) ₂-) (seeing accompanying drawing 2) confirm as hexichol first sulfydryl two monofluoroacetamides (total recovery 58.2%), fusing point=114.5～114.9 ℃.

3, the preparation of modafinil fluorine-containing analogue

In the 50mL there-necked flask, add successively hexichol first sulfydryl two monofluoroacetamides (0.3g, 1mmol), methylene dichloride (10mL), slowly splash under the stirring at room hydrogen peroxide (30%, 3mL), drip the airtight stirring in back, analyse a plate monitoring reaction progress with silica gel thin-layer.After 10 hours, steaming desolventizes, and the crude product that obtains is with column chromatography (PE: EA=2: 1) remove impurity, revolve and boil off solvent, obtain white solid 270mg (total recovery 56.8%).Product is through nucleus magnetic hydrogen spectrum: ¹H NMR (CDCl ₃500MHz) δ: 5.51 (1H, s ,-CH-S-), 5.76 (1H, s ,-NH ₂), 6.49 (1H, s ,-NH ₂), 7.38～7.49 (10H, m, (C ₆H ₅) ₂-CH) be accredited as target compound-modafinil fluorine-containing analogue (seeing accompanying drawing 3).Called after: benzhydrylsulfinyl base two monofluoroacetamides.

Claims (2)

1, a kind of modafinil fluorine-containing analogue is characterized in that molecular structural formula is as follows:

2, according to the synthetic method of a kind of modafinil fluorine-containing analogue of claim 1 art, it is characterized in that may further comprise the steps:

1) the Bromodifluoroacetic acid ethyl ester is mixed with ether and fully after the dissolving, be cooled to about 0 ℃ at ice-water bath, stir and feed the exsiccant ammonia down, react to revolve after 8-9 hour and steam except that desolvating, the sherwood oil recrystallization obtains bromine two monofluoroacetamides;

2) two beneze methane thiols are mixed with dimethyl sulfoxide (DMSO) and fully after the dissolving, stir and add NaH down, exothermic heat of reaction, after temperature is reduced to about 22 ℃, slowly add bromine two monofluoroacetamides, after stirring reaction 10-14 hour, in reaction solution, add ammonium chloride saturated aqueous solution and regulate PH ≈ 7.0, through extraction, washing organic phase, drying, revolve to steam to remove and obtain hexichol first sulfydryl two monofluoroacetamides after desolvating;

3) hexichol first sulfydryl two monofluoroacetamides are mixed with methylene dichloride, stir down and slowly splash into hydrogen peroxide, after airtight stirring 9-10 hour, steaming desolventizes, and the crude product that obtains is removed impurity with column chromatography, revolves to steam to remove to desolvate again, and promptly gets modafinil fluorine-containing analogue.

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