CN1155280A - Process for synthesizing 5-(3-[exo-bicyclo(2,2,1)]-hept-2-yloxyl]-4-methoxyphenyl)-3-4,5,6-tetrahydropyrimidin-2(1H)-one - Google Patents
Process for synthesizing 5-(3-[exo-bicyclo(2,2,1)]-hept-2-yloxyl]-4-methoxyphenyl)-3-4,5,6-tetrahydropyrimidin-2(1H)-one Download PDFInfo
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Abstract
This invention relates to novel processes for preparing the pharmaceutically active compound 5-(3-[(2S)-exo-bicyclo[2.2.1]hept-2-yloxy]-4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2(1H)-one and its corresponding 2R enantiomer and for preparing certain intermediates used in the synthesis of these compounds. It also relates to novel intermediates used in the synthesis of such pharmaceutically active compounds and to other novel compounds that are related to such intermediates.
Description
Background of invention
The present invention relates to prepare pharmaceutical active compounds 5-(3-[(2S)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-3,4,5, the novel method of 6-tetrahydropyrimidine-2 (1H)-ketone and its corresponding 2R enantiomorph and preparation are used for the novel method of some synthetic intermediate of these compounds.The invention still further relates to the synthetic new intermediate that is used for these pharmaceutical active compounds and relate to other novel cpd relevant with these intermediates.
International Patent Application WO 87/06576 (announcement on November 5th, 1987) relate to 5-(3-[(2-is outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone, and claim that it can be used as antidepressive.International Patent Application WO 91/07178 (announcement on May 30th, 1991) relates to the purposes of this compound aspect treatment asthma, inflammatory airway disease and dermatosis.
US patent 5,270,206 (announcements on December 14th, 1993) relate to preparation (+)-(2R)-Nei-norborneol and (are also referred to as (2R)-Nei-dicyclo [2.2.1] heptan-2-alcohol or (1S, 2R, 4R)-dicyclo [2.2.1] heptan-2-alcohol) and (-)-(2S)-Nei-norborneol (be also referred to as (2S)-Nei-dicyclo [2.2.1] heptan-2-alcohol or (1R, 2S, 4S)-dicyclo [2.2.1] heptan-2-alcohol) method, with relate to them and further change into pharmaceutically active agents 5-(3-[(2S)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone, as follows;
And 5-(3-[(2R)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone, as follows,
Here the All Files of being quoted comprises those of front, and it is for reference that their full content is introduced into this paper.
Summary of the invention
The present invention relates to have the compound of following formula
Wherein X is identical with Y and is selected from-CN-CO
2(C
1-C
6) alkyl ,-CONH
2With-CONHOH, or X and Y connect together and form the group of following formula
The invention still further relates to compound with following general formula
R wherein
1And R
2Be independently selected from (C
1-C
6) alkyl and hydrogen.
The invention still further relates to the compound of following general formula
With
Each R wherein
2Be independently selected from (C
1-C
6) alkyl.
The invention still further relates to the method for the compound of preparation following formula
Wherein X is identical with Y and is selected from-CN-CO
2(C
1-C
6) alkyl ,-CONH
2With-CONHOH, or X and Y connect together and form the group of following formula
This method comprises: (1) allows 3-hydroxyl-4-methoxybenzaldehyde and general formula X CH
2CO
2The compound of H (wherein X as defined above) reacts in the presence of alkali (preferred tertiary amine), and obtaining wherein, X and Y are-CN-CO simultaneously
2(C
1-C
6) alkyl ,-CONH
2Or-compound of the general formula I I of CONHOH; Perhaps (2) (a) allow wherein X and Y are simultaneously-general formula I I compound and hydrogen peroxide (the preferred hydrogen peroxide alkaline aqueous solution) reaction of CN, form wherein two-CN group all by-CONH
2The corresponding bisamide of alternate; (b) with oxygenant (for example, two (acetoxyl group) phenyl-iodide, two (trifluoroacetyl oxygen base) phenyl-iodide, NaOCl, NaOBr or lead tetraacetate) bisamide that forms in the step (a) being carried out Huffman (Hoffman) resets to form corresponding double carbamate; (c) allow middle double carbamate that forms of step (b) and alkali (for example, the alkali metal alcoholates or the alkali metal hydroxide that contain 1-6 carbon atom) reaction, form the connect together ring urea of the group that constitutes general formula " a " of wherein X and Y, explain as above.
The invention still further relates to the method for the compound of the following general formula of preparation,
Or
Wherein X and Y are the same with definition among the above general formula I I, this method comprise allow general formula I I compound defined above respectively with R-(+)-Nei-norborneol or S-(-)-Nei-norborneol, triaryl or trialkyl phosphine and azodicarboxylate react.
The invention still further relates to the method for the compound of the following general formula of preparation,
Or
Wherein X is identical with Y and is selected from-CN-CONH
2,-CO
2(C
1-C
6) alkyl and-CONHOH, or X and Y connect together and form the group of following formula
This method comprises: (1) allows 3-hydroxyl-4-methoxybenzaldehyde and general formula X CH
2CO
2The compound of H reacts in the presence of alkali (preferred tertiary amine), and wherein X is-CN ,-CO
2(C
1-C
6) alkyl ,-CONH
2Or-CONHOH, form the compound of following general formula I I
Wherein X is identical with Y and is selected from-CN-CONH
2,-CO
2(C
1-C
6) alkyl and-CONHOH; Perhaps (2) (a) allow wherein X and Y are simultaneously-general formula I I compound and the hydroperoxidation of CN, form wherein two-CN group all by-CONH
2The corresponding bisamide of alternate; (b) with oxygenant (for example, two (acetoxyl group) phenyl-iodide, two (trifluoroacetyl oxygen base) phenyl-iodide, NaOCl, NaOBr or lead tetraacetate) bisamide that forms in the step (a) being carried out Huffman (Hoffman) resets to form corresponding double carbamate; (c) allow the double carbamate that forms in the step (b) react, form the connect together ring urea of group of the following general formula of formation of wherein X and Y with alkali (for example, containing the alkali metal alcoholates of 1-6 carbon atom),
Then (3) allow the described general formula I I compound that forms in above step 1 or 2 respectively with R-(+)-Nei-norborneol or S-(-)-Nei-norborneol, triaryl or trialkyl phosphine and azodicarboxylate's reaction.
The invention still further relates to the method for the compound of the following general formula of preparation
Or
R wherein
1And R
2Be independently selected from hydrogen and (C
1-C
6) alkyl, this method comprises, allows the compound of following general formula
Or
With the diacetoxy phenyl-iodide, NaOZ and Z ' OH react respectively, and wherein Z and Z ' are independently selected from hydrogen and (C
1-C
6) alkyl.
The invention still further relates to the method for the compound of the following general formula of preparation
Or
Comprise and allow the compound of following general formula
Or
R wherein
1And R
2Be independently selected from hydrogen and (C
1-C
6) alkyl, the compound with general formula NaOZ and Z ' OH reacts respectively, and wherein Z and Z ' are independently selected from hydrogen and (C
1-C
6) alkyl.
The invention still further relates to the method for the compound of the following general formula of preparation
Or
Comprise: allow the compound of following general formula
Or
With the diacetoxy phenyl-iodide, NaOZ and Z ' OH react respectively, and wherein Z and Z ' are independently selected from hydrogen and (C
1-C
6) alkyl, the intermediate of the following general formula of formation
Or
R wherein
1And R
2Be independently selected from hydrogen and (C
1-C
6) alkyl; Then or (b1) isolate the intermediate of described general formula V or V ' and allow the compound reaction of it and general formula NaOZ and Z ' OH, wherein Z and Z ' are as defined above; Perhaps (b2) allow described general formula V or V ' intermediate on the spot with the reaction of the compound of general formula NaOZ and Z ' OH, wherein Z and Z ' are as defined above.
Here employed phrase " reaction-inert solvent " refers to not with a kind of mode and interactional solvent of starting raw material, reagent, intermediate or product that influences the productive rate of required product unfriendly.
Employed term " alkyl ", comprise have straight chain, the saturated univalence hydrocarbyl of side chain or circular part or their combination, except as otherwise noted.
Above general formula I I comprises the compound identical with those cited compounds with V and V ', but for except following these situations: one or more hydrogen, carbon, nitrogen or Sauerstoffatom are substituted by its radioactivity or stable isotropic substance.These radiolabeled compounds can be used as scientific research and the diagnostic tool in the metabolic drug dynamics research and in binding analysis.
Detailed description of the present invention
Method of the present invention and the method for preparing novel cpd of the present invention have been described in reaction mechanism below and the discussion.Except as otherwise noted, reaction mechanism below and in question substituent X, Y, R, R
1, R
2, R
3And R
4, group " (a) " and general formula I I, III, III ', IV, IV ', V, V ', VI and VI ' are as defined above.
Reaction mechanism 1
Reaction mechanism 2
Reaction mechanism 2A
Reaction mechanism 2A (continuing)
Reaction mechanism 3
Reaction mechanism 3 (continuing)
Reaction mechanism 1 has illustrated the preparation method of the compound of general formula I I and III.Reaction mechanism 2 illustrated general formula V compound the preparation method and from wherein X and Y be simultaneously-compound of formula III of CN prepare 5-(3-[(2S)-outside-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-3,4,5, the method for 6-tetrahydropyrimidine-2 (1H)-ketone (compound VI).(wherein X and Y are simultaneously-this compound of the general formula III of CN hereinafter is called the compound of general formula III A in reaction mechanism 2 neutralizations).Reaction mechanism 3 has illustrated from wherein X and Y are-CO simultaneously
2(C
1-C
6) alkyl or-compound of formula III of CONHOH prepares the method for general formula VI compound.(wherein X and Y are-CO simultaneously
2(C
1-C
6) alkyl or-compound of formula III of CONHOH hereinafter is called the compound of general formula III B or IIIC respectively in reaction mechanism 3 neutralizations).
Referring to reaction mechanism 1, in the presence of alkali (preferred tertiary amine), in reaction-inert solvent, allow the general formula X CH of isovanillin (Compound I) and two molar equivalents
2CO
2The compound of H carries out condensation, and wherein X is-CN ,-CO
2(C
1-C
6) alkyl ,-CONH
2With-CONHOH, Nuo Wengeer in order-Mitchell reacts (Knoevenagel-Michael) mode and follows decarboxylic reaction, obtains general formula I I compound, and wherein X is institute's specified value in the above definition identical and that be selected from X with Y.This reaction can be carried out under the temperature between about 10 ℃-Yue 130 ℃.Preferably approximately carries out this reaction under reflux temperature.Suitable solvent includes, but not limited to N-methylmorpholine, triethylamine, pyridine, and non-alkali reaction inert solvent such as tetrahydrofuran (THF) (THF), dimethyl formamide (DMF), acetonitrile and toluene.Preferably, secondary amine (for example piperidines or tetramethyleneimine) also adds as catalyzer.In a preferred embodiment of this reaction, N-methylmorpholine is used as solvent/alkali and piperidines also is added in the reaction mixture.
Wherein X and Y connect together the general formula I I compound (promptly encircling urea) that forms group " a " can X and Y be simultaneously by allowing wherein-the general formula I I compound of CN carry out a series of in reaction mechanism 2 reaction explanation and that will describe in this application subsequently prepare.
The general formula I I compound that forms in above reaction is converted to corresponding compound of formula III by the following method: under the Mitsunobu condition, and R-(+)-Nei-norborneol that allows general formula I I compound and represent below
Or in the S-that represents below-norborneol
Carry out coupled reaction, had accordingly respectively opposite stereochemistry (by in this-norborneol reactant decision) general formula III or III ' compound.Therefore, if use in the R--norborneol, product will be have " S " if the compound of formula III of configuration and using in the S--norborneol, product will be the general formula III ' compound with " R " configuration.
This reaction is normally carried out in the presence of as triphenylphosphine or tributylphosphine and azodicarboxylate's oxygenant at triaryl or trialkyl phosphine.In general, it also can be under about 10 ℃-Yue 150 ℃ temperature, preferably approximately under reflux temperature, at aprotonic solvent such as tetrahydrofuran (THF) (THF), acetonitrile, methylene dichloride, DMF in toluene and the benzene, carries out among the preferred THF.Suitable azo-compound comprises azo-2-carboxylic acid's diisopropyl ester, azo dicarbapentaborane two piperidines and azo-2-carboxylic acid's diethyl ester.Azo-2-carboxylic acid's diisopropyl ester and azo dicarbapentaborane two piperidines are preferred.
The general formula III that forms in above step or the stereochemistry of III ' compound are retained in the step of all back, as shown in reaction mechanism 2 and 3.
As already pointed out, reaction mechanism 2 has illustrated that the compound of general formula III A changes into the method for general formula VI compound.Referring to reaction mechanism 2, general formula III A compound hydrogen peroxide (preferred hydrogen peroxide alkaline aqueous solution) hydrolysis, the bisamide of formation general formula I V.This reaction is in polar solvent such as acetone, ethanol, Virahol or butanone (wherein acetone is preferred) usually, and (wherein approximately room temperature is preferred) carries out under about 0 ℃-Yue 100 ℃ temperature.Yellow soda ash or another kind of inorganic salt with similar alkalescence can join in the reaction mixture to promote reaction.
So the general formula I V compound that forms carries out Hoffmann rearrangement reaction then, and wherein two carboxylacyl amine groups are transformed into the carbamate groups (nitrogen moves) of general formula V.Can use suitable oxygenant, comprise two (acetoxyl group) phenyl-iodides, two (trifluoroacetyl oxygen base) phenyl-iodide, NaOCl, NaOBr or lead tetraacetate.Two (acetoxyl group) phenyl-iodide is preferred.This reaction is carried out in the presence of alkali usually.When using two (acetoxyl group) phenyl-iodide, acceptable alkali comprises alkali-metal oxyhydroxide and (C
1-C
6) alkoxide.Temperature of reaction can be approximately-20 ℃ to about 100 ℃, about 0 ℃ extremely about 25 ℃ temperature be preferred.The example of suitable reaction-inert solvent is (C
1-C
6) alkanol, THF, DMF and acetonitrile.
Final step in this sequence is the base catalysis closed loop of the double carbamate of general formula V, forms the symmetry pyrimid-2-one of general formula VI.This reaction can be carried out and preferably carry out under reflux temperature under the temperature between about 0 ℃ to about 100 ℃.Suitable solvent includes, but not limited to lower alcohols, and methyl alcohol is preferred.Suitable bases comprises the alkali metal alcoholates that contains 1-6 carbon atom.Preferred alkali is sodium methylate.
In addition, last two steps of this sequence can be finished according to the mode that merges under the situation of not isolating double carbamate V.This improvement is equal to the narration of the relevant hofmann rearrangement in front basically.Preferably this is reflected under the solvent refluxing temperature and carries out.Also preferably additional alkali is joined in the reaction mixture.Acceptable oxygenant, alkali and choice of Solvent scope are with foregoing identical.Two (acetoxyl group) phenyl-iodide, sodium methylate and methyl alcohol have been used in preferred reaction.
The reaction of the compound of the compound formation general formula VI of general formula V as previously discussed, can be undertaken by in the intermediate of general formula VII as shown in reaction mechanism 2A and VIII one or both.
Wherein X and Y are-CONH simultaneously
2Compound of formula III identical with general formula I V compound, thereby can illustrated method change into compound (VI) with the former in the reaction mechanism 2 by using.
By using illustrated method in the reaction mechanism 3, wherein X and Y be simultaneously-CONHOH or-CO
2(C
1-C
6) compound of formula III of alkyl can change into the compound of general formula VI.
Referring to reaction mechanism 3, the diester of general formula III B and hydroxylamine hydrochloride react in the presence of alkali (for example tertiary amine base), form the hydroxamic acid of general formula III C.This reaction can be in the various reaction-inert solvents that do not have intensive nucleophilic characteristic under about 0 ℃-Yue 100 ℃ temperature, preferably under about 20 ℃, carry out, these solvents include, but not limited to lower alcohols, ring-type and acyclic ethers (for example ether or THF), neutral aromatic substance such as benzene and toluene, DMF, N,N-DIMETHYLACETAMIDE, ethyl acetate, acetonitrile and water.
Then under about 0 ℃-Yue 100 ℃ temperature, preferably under about 20 ℃, can be by using with the conditioned disjunction reagent of dehydration of alcohols, the hydroxamic acid of resetting general formula III C through Loessen changes into compound VI.Preferred reagent is Tosyl chloride.In addition, can also form the different esters of hydroxamic acid, finish on the spot to arbitrariness and, this ester be changed into the compound of general formula VI through heat and/or acid treatment then by using well-known in the art method.
There is not specially the preparation of other compound of the present invention of describing in the experimental section in front to finish by the combination of using in the art skilled person above-mentioned reaction fully aware of.
That in above reaction mechanism, discussed or the explanation each the reaction in, pressure is not strict, except as otherwise noted.The atmospheric pressure of about 0.5 normal atmosphere-Yue 3 generally is acceptable, and environmental stress, and promptly about 1 normal atmosphere is saying it is preferred on the meaning easily.
Method of the present invention and product can be used for the synthetic of pharmaceutical active compounds VI and VI '.The racemic mixture of compound VI and VI ' and these compounds (below be generically and collectively referred to as " active compound ") can be used for treating dysthymia disorders, asthma, inflammatory airway disease and dermatosis (for example psoriasis and atopic dermatitis).
Active compound is the c-AMP phosphodiesterase inhibitor that does not rely on calcium.The ability of these compounds inhibition c-AMP phosphodiesterase can be by Davis, biological chemistry and biophysical journal (Biochimica et Biophysica.Acta.), and 797, the method for 354-362 (1984) is measured.
The antidepressant activity of active compound can be by people such as Porsult, international pharmacodynamics magazine (Arch.Int.Pharmacodvn.), 227, the desperate example (behavioral despair paradigm) of the behavior that 327-336 (1977) describes and by people such as Roe, pharmacological testing therapeutics magazine (J.Pharmacol.Exp.Therap.), 226,686-700 (1983) describes is used for the determination test medicine resist ability that serpentine lowers the temperature in mouse body method and measures.
When being used for the treatment of dysthymia disorders, active compound itself can use or use with the pharmaceutical compositions that comprises acceptable carrier on active compound and the pharmacology or thinner.For oral, a kind of optimization approach of using active compound, suitable pharmaceutical carrier comprises inert diluent or filler, thereby forms dosage form such as tablet, pulvis, capsule and similar medicament.If desired, these pharmaceutical compositions contain additional composition, as seasonings, binding agent, vehicle and analogue.For example, the tablet that contains various vehicle such as Trisodium Citrate cooperates silicate and binding agent such as Polyvinylpyrolidone (PVP), sucrose, gelatin and gum arabic to use with various disintegrating agents such as starch, alginic acid and some.In addition, lubricant such as Magnesium Stearate, sodium lauryl sulphate and talcum usually are used to make tablet.The solids composition of similar type also is used as filler in the gelatine capsule of soft hard filling.Its preferable material is lactose or toffee and high molecular weight polyethylene glycol.
For oral, dosage every day of promoting agent is the about 10mg of about 0.1mg-and for parenteral administration, preferred i.v. or i.m., the about 5mg of about 0.01mg-.The pharmacist can determine as much as possible certainly for given people's suitable dose, this dosage depends on patient's the seriousness of symptom and the patient factors such as reaction to concrete medicine.
About in the body of purposes of active compound in asthma and skin diseases treatment and in vitro tests in International Patent Application WO 91/07178 at the 4th and 5 page of specification sheets with in embodiment 1-3, discuss, for reference with above relevant this paper that also all is introduced into.
In the systematic treating with a kind of asthma of active compound or inflammatory dermatosis, dosage generally is about 0.01-2 milligram/kg/day (0.5-100 mg/day, the general population that body weight is 50 kilograms), and is once or the gradation administration, irrelevant with route of administration.Certainly, depend on the concrete compound and the specific nature of each disease, the dosage beyond this scope will be stipulated under the judgement in care physician.Asthma treatment in, intranasal administration (drops or sprays), the suction of aerosol through port and common oral generally be preferred.Yet, if patient can't swallow, or mouthful absorb and to be affected, the preferred systems drug delivery route be parenteral route (i.m., i.v.).In the treatment of inflammatory dermatosis, preferred route of administration is oral or topical application.In inflammatory airway treatment of diseases, preferred route of administration is that nose is interior or oral.
This active compound is generally used with the pharmaceutical compositions that contains acceptable carrier on a kind of and pharmacology in this compound or thinner.Said composition is generally according to known way, prepares by using the solid that adapts with required method of application or liquid vehicle or thinner: for oral, and with tablet, hard or soft gelatin capsule, suspension, granula, forms such as pulvis; For parenteral administration, with forms such as injectable solution or suspension; For topical application,, generally contain the active compound of the 0.1-1% that has an appointment (w/v) with forms such as solution, lotion, paste, ointment; With in the nose or sucker use, generally with 0.1-1% (w/v) solution form.
The present invention is illustrated by the following examples.Yet, should be appreciated that the present invention is not limited to the specific detail of these embodiment.
Embodiment 1
3-(3-hydroxyl-4-p-methoxy-phenyl)-pentane-1, the 5-dintrile
To contain isovanillin (30.4g, 200mmol) and cyanoacetic acid (68.0g, a kind of solution of forming by 3.0ml (30mmol) piperidines and 151mlN-methylmorpholine of packing in 500ml flask 800mmol).The yellow slurry heating that forms at first made it gentle reflux 21 hours and be cooled to room temperature then and concentrated on rotatory evaporator.Resulting brown oil is dissolved in the 430ml ethyl acetate (EtOAc) order water (H
2O) washing, 5 equivalent liquid degree hydrochloric acid (5N HCl) and H
2The O washing, the water that washes out is stripped with ethylene dichloride after merging again.The organic layer merging is obtained the heavy-gravity orange oil with removing to desolvate then, and it is again from ethyl acetate/dichloromethane (EtOAc/CH
2Cl
2) middle crystallization, after filtration and drying, obtain 38.3g orange solids thing.Obtain 35.3g (82%) light yellow solid, m.p.90-92 ℃ from EtOAc/ Di Iso Propyl Ether recrystallization.
Embodiment 2
3-(3-[(2S)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-1,5-pentane dintrile
At room temperature to contain R-(+)-Nei-norborneol (1.12g, 10.0mmol), 3-(3-hydroxyl-4-p-methoxy-phenyl)-pentane-1,5-dintrile (4.33g, 20mmol) and triphenylphosphine (TPP) (3.93g, adding 1,1 in tetrahydrofuran (THF) 15mmol) (THF) solution (20ml) '-(azo dicarbapentaborane)-two piperidines (ADDP) (3.78g, 15mmol).Resulting brown slurry reflux 12 hours is used 10mlTHF and 30ml dilution with toluene then, is cooled to room temperature and granulation 30 minutes.After removing by filter reductive ADDP, twice usefulness 20ml of filtrate 1N sodium hydroxide (NaOH) washing and remaining organic phase and 0.2g gac and 20g sodium sulfate (Na
2SO
4) stir together, filter and be condensed into heavy-gravity dark-brown oil.Recrystallization obtains the pale solid of 2.34g (75%) from isopropanol/hexane, m.p.126-127 ℃.
Embodiment 3
3-(3-[(2S)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-pentane-1.5-dintrile
To containing norborneol (2.243g, 20.0mmol) and triphenylphosphine (5.272g, 20.10mmol) THF (30ml) reflux solution in add second kind and contain 3-(3-hydroxyl-4-p-methoxy-phenyl)-pentane-1,5-dintrile (4.350g, 20.10mmol) and azo-2-carboxylic acid's diisopropyl ester (DIAD) (4.044g, THF solution 21.00mmol).Mixture heating up refluxed 18 hours, cooling and concentrate on rotatory evaporator and be dissolved in then in the 60ml toluene.Twice usefulness 1N of resulting brown toluene solution NaOH washing through dried over sodium sulfate, is filtered then and is concentrated and obtain the 18g beige solid.Obtain 4.26g (69%) white solid, m.p.127-128 ℃ from 1/1 isopropanol/hexane recrystallization.
Embodiment 4
3-(3-[(2S)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl) glutaramide
To 3-(3-[(2S)-outside-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-pentane-1, the 5-dintrile (10% aqueous sodium carbonate (Na that adds 24ml among the 2.29g, (6 ℃) acetone solns of refrigerative 7.38mmol) (46ml)
2CO
3) (23mmol), add 5.2ml 30% hydrogen peroxide (H then
2O
2).Resulting slurry at room temperature stirred 4 days, with additional 1.7ml 30%H
2O
2Handle and and then stirred 2 days.By adding 4 normal sodium bisulfite (NaHSO
3) make unnecessary peroxide breakdown and dry on rotatory evaporator its volume is reduced to about 80ml.The heavy-gravity slurry is used the dense HCl acidifying of 6.5ml then, with dense ammonium hydroxide (NH
4OH) neutralize and be condensed to the volume of about 50ml.Filtration and vacuum-drying obtain 2.20g (86%) white solid, m.p.161-163 ℃.
Embodiment 5
5-(3-[(2S)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone
(43.60g added the solution of 152ml 25% sodium methylates (NaOMe) in methyl alcohol through 10 minutes in (2 ℃) methyl alcohol of cooling 133mmol) (MeOH) suspension (40ml) to the diacetoxy phenyl-iodide.After 3 ℃ are stirred 20 minutes down, with 3-(3-[(2S)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl) glutaramide (22.98g, 66.5mmol) add as the precooling slurry in 45ml methyl alcohol, be warming up to room temperature through 3 hours then and react, postheating refluxed 45 minutes.Slurry is cooled to room temperature, with 152ml 25%NaOMe solution-treated and the reflux 16 hours in MeOH.Condenser is replaced with still head then and removes 350ml MeOH.Resulting slurry is cooled to 12 ℃, uses 200ml CH
2Cl
2With 100ml H
2O
2Dilution and neutralizing with dense HCl then.Each layer is separated from each other and uses CH
2Cl
2Twice aqueous layer extracted obtains 3 organic layers, they merged, through sodium sulfate (Na
2SO
4) drying, filter and the concentrated then 39g light orange solid that obtains.In backflow EtOAc, make slurry again, finally obtain 15.48g white solid (77%), m.p.199-200 ℃.
Embodiment 6
N, N '-dimethoxy carbonyl-2-(3-[(2S)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-1, the 3-propylene diamine
To 3-(3-[(2S)-outside-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl) glutaramide (0.346g, 1.00mmol) add 0.140g potassium hydroxide (KOH) (2.50mmol) in cooling (0 ℃) suspension in 1.75ml MeOH, add 0.657g (3.0mmol) diacetoxy iodobenzene subsequently.Allow resulting slightly yellowy solution be warming up to room temperature, stirred 80 minutes and on rotatory evaporator, be condensed into then mashed prod.Water with this substance transfer in separating funnel and use CH
2Cl
2Extracting twice.The organic layer that merges filters and concentrates through dried over sodium sulfate, obtains the impure required double carbamate of yellow spumescence of 0.506g (125%).Thin-layer chromatographic analysis (TLC): R
f=0.74,9: 1CH
2Cl
2Among/the MeOH.It is 406 main peak that gas chromatography-mass spectrometry demonstrates molion, and it is the molecular weight of title compound.
Embodiment 7
5-(3-[(2R)-outer-dicyclo [2.2.1] heptan-2-base oxygen base]-the 4-p-methoxy-phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H)-ketone
(98mg 0.2mmol) is dissolved among the MeOH (0.5ml), handles and refluxes 18 hours with 0.5ml 25%NaOMe (in MeOH) from the thick double carbamate foam of embodiment 6.Remove desolvate after, resulting solid is soluble in water, uses CH
2Cl
2Extracting twice, the organic layer of merging is through sal epsom (MgSO
4) drying.The filtration of filtrate and the concentrated needed urea that obtains the yellow solid form of 48mg (75%).Thin-layer chromatographic analysis (TLC): R
f=0.57,9: 1CH
2Cl
2Among/the MeOH.
Claims (27)
1. method for preparing the compound of following general formula
Comprise:
(a) allow the compound of following general formula
Or
With the diacetoxy phenyl-iodide, NaOZ and Z ' OH react respectively, and wherein Z and Z ' are independently selected from hydrogen and (C
1-C
6) alkyl, the intermediate of the following general formula of formation
R wherein
1And R
2Be independently selected from hydrogen and (C
1-C
6) alkyl; Then or (b1) isolate the intermediate of described general formula V or V ' and allow the compound reaction of it and general formula NaOZ and Z ' OH, wherein Z and Z ' are as defined above; Perhaps (b2) allow described general formula V or V ' intermediate on the spot with the reaction of the compound of general formula NaOZ and Z ' OH, wherein Z and Z ' are as defined above.
2. method for preparing the compound of following general formula
Or
Wherein X is identical with Y and is selected from-CN-CONH
2,-CO
2(C
1-C
6) alkyl and-CONHOH, or X and Y connect together and form the group of following formula
This method comprises: (1) allows 3-hydroxyl-4-methoxybenzaldehyde and general formula X CH
2CO
2The compound of H reacts in the presence of alkali, and wherein X is-CN ,-CO
2(C
1-C
6) alkyl ,-CONH
2Or-CONHOH, form the compound of following general formula I I
Wherein X is identical with Y and is selected from-CN-CONH
2,-CO
2(C
1-C
6) alkyl and-CONHOH; Perhaps (2) (a) allow wherein X and Y are simultaneously-general formula I I compound and the hydroperoxidation of CN, form wherein two-CN group all by-CONH
2The corresponding bisamide of alternate; (b) with oxygenant the bisamide that forms in the step (a) is carried out hofmann rearrangement to form corresponding double carbamate; (c) allow double carbamate and the alkali reaction that forms in the step (b), form the connect together ring urea of the group that constitutes following general formula of wherein X and Y,
Then (3) allow the described general formula I I compound that forms in above step 1 or 2 respectively with triaryl or trialkyl phosphine, azodicarboxylate, and R-(+)-Nei-norborneol or S-(-)-Nei-norborneol reaction.
3. according to the method for claim 2, wherein said alkali is tertiary amine.
4. according to the method for claim 2, wherein tertiary amine and secondary amine are joined in the reaction mixture simultaneously.
5. according to the method for claim 4, wherein tertiary amine is selected from N-methylmorpholine, triethylamine, and pyridine and diisopropylamine and secondary amine are selected from piperidines and tetramethyleneimine.
6. according to the method for claim 2, wherein the azodicarboxylate is selected from azo-2-carboxylic acid's diisopropyl ester and azo dicarbapentaborane two piperidines.
7. according to the method for claim 2, wherein triaryl phosphine is a triphenylphosphine.
8. method for preparing compound with following general formula
Or
Comprise and allow the compound of following general formula
Or
R wherein
1And R
2Be independently selected from hydrogen and (C
1-C
6) alkyl, the compound with general formula NaOZ and Z ' OH reacts respectively, and wherein Z and Z ' are independently selected from hydrogen and (C
1-C
6) alkyl.
9. compound with following general formula
Wherein X is identical with Y and is selected from-CO
2(C
1-C
6) alkyl ,-CONH
2With-CONHOH, or X and Y connect together and form the group of following general formula
10. according to the compound of claim 9, wherein X and Y are-CONH simultaneously
2
11. according to the compound of claim 9, wherein X and Y connect together and form the group of following general formula.
12. according to the compound of claim 9, wherein X and Y are-CO simultaneously
2(C
1-C
6) alkyl.
13. according to the compound of claim 9, wherein X and Y are-CONHOH simultaneously.
14. compound with following general formula
Or
R wherein
1And R
2Be independently selected from (C
1-C
6) alkyl and hydrogen.
15. according to the compound of claim 14, wherein R
1And R
2Be selected from (C simultaneously
1-C
6) alkyl.
16. according to the compound of claim 14, wherein R
1And R
2Be hydrogen simultaneously.
17. method for preparing the compound of following general formula
Wherein X is identical with Y and is selected from-CO
2(C
1-C
6) alkyl ,-CONH
2With-CONHOH, or X and Y connect together and form the group of following formula
This method comprises: (1) allows 3-hydroxyl-4-methoxybenzaldehyde and general formula X CH
2CO
2The compound of H reacts in the presence of alkali, and wherein X is selected from-CO
2(C
1-C
6) alkyl ,-CONH
2With-CONHOH, obtaining wherein, X and Y are-CO simultaneously
2(C
1-C
6) alkyl ,-CONH
2Compound with the general formula I I of-CONHOH; Perhaps (2) (a) allow wherein X and Y are simultaneously-general formula I I compound and the hydroperoxidation of CN, form wherein two-CN group all by-CONH
2The corresponding bisamide of alternate; (b) with oxygenant the bisamide that forms in the step (a) is carried out hofmann rearrangement to form corresponding double carbamate; (c) allow double carbamate and the alkali reaction that forms in the step (b), form the connect together ring urea of the group that constitutes following general formula of wherein X and Y.
18. according to the method for claim 17,3-hydroxyl-4-methoxybenzaldehyde and HOOCCH wherein
2The CONHOH reaction.
19. according to the method for claim 17,3-hydroxyl-4-methoxybenzaldehyde and HOOCCH wherein
2CONH
2Reaction.
20. according to the method for claim 17,3-hydroxyl-4-methoxybenzaldehyde and HOOCCH wherein
2CO
2(C
1-C
6) alkylation reaction.
21. according to the method for claim 17, wherein said alkali is tertiary amine.
22., wherein simultaneously tertiary amine and secondary amine are joined in the reaction mixture according to the method for claim 17.
23. according to the method for claim 22, wherein said secondary amine is piperidines or tetramethyleneimine.
24. method for preparing the compound of following general formula
Or
Wherein X is identical with Y and is selected from-CN-CONH
2,-CO
2(C
1-C
6) alkyl and-CONHOH, or X and Y connect together and form the group of following formula
This method comprises allows the compound of following general formula
Wherein X and Y are identical and as defined above, respectively with triaryl or trialkyl phosphine, and azodicarboxylate and R-(+)-Nei-norborneol or S-(-)-Nei-norborneol reaction.
25. method for preparing the compound of following general formula
Or
R wherein
1And R
2Be independently selected from hydrogen and (C
1-C
6) alkyl, this method comprises, allows the compound of following general formula
With the diacetoxy phenyl-iodide, NaOZ and Z ' OH react respectively, and wherein Z and Z ' are independently selected from hydrogen and (C
1-C
6) alkyl.
26. according to the method for claim 25, further comprise allowing the compound of described general formula V or V ' and the reaction of compound that general formula is ZONa and Z ' OH, wherein Z and Z ' such as in the claim 25 definition, obtain the compound of following general formula respectively
Or
27. compound with following general formula
Or
Each R wherein
2Be independently selected from (C
1-C
6) alkyl.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 95194538 CN1155280A (en) | 1994-08-05 | 1995-05-04 | Process for synthesizing 5-(3-[exo-bicyclo(2,2,1)]-hept-2-yloxyl]-4-methoxyphenyl)-3-4,5,6-tetrahydropyrimidin-2(1H)-one |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/286,579 | 1994-08-05 | ||
| CN 95194538 CN1155280A (en) | 1994-08-05 | 1995-05-04 | Process for synthesizing 5-(3-[exo-bicyclo(2,2,1)]-hept-2-yloxyl]-4-methoxyphenyl)-3-4,5,6-tetrahydropyrimidin-2(1H)-one |
Related Child Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN03104212A Division CN1431195A (en) | 1994-08-05 | 2003-01-30 | Synthesis of 5-(3-[exo-dicyclo [2,2,1] heptyl-2-ylidene oxy]-4-methoxy phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H) ketonic intermediate and its prepn. process |
| CN03104211A Division CN1431194A (en) | 1994-08-05 | 2003-01-30 | Synthesis of 5-(3-[exo-dicyclo [2,2,1] heptyl-2-ylidene oxy]-4-methoxy phenyl)-3,4,5,6-tetrahydropyrimidine-2 (1H) ketonic intermediate, and its prepn. process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1155280A true CN1155280A (en) | 1997-07-23 |
Family
ID=5082749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 95194538 Pending CN1155280A (en) | 1994-08-05 | 1995-05-04 | Process for synthesizing 5-(3-[exo-bicyclo(2,2,1)]-hept-2-yloxyl]-4-methoxyphenyl)-3-4,5,6-tetrahydropyrimidin-2(1H)-one |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1155280A (en) |
-
1995
- 1995-05-04 CN CN 95194538 patent/CN1155280A/en active Pending
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