CN1185782A - 2-azabicyclo [2,2,1] heptane derivatives, preparation and application thereof - Google Patents
2-azabicyclo [2,2,1] heptane derivatives, preparation and application thereof Download PDFInfo
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Abstract
Novel 1R or 1S 2-azabicyclo [2, 2,1] heptane derivatives of general formula (I) or (I'), wherein R is a hydrogen atom or a radical of formula (II) or (II'), where R[1] is an alkyl radical containing 1-4 carbon atoms and Ar is an optionally substituted phenyl or Alpha-or Beta- naphthyl radical, and preparation and application thereof. The novel products of general formula (I) are particularly useful for preparing adenosine agonists.
Description
The present invention relates to 2-azabicyclo [2,2,1] the heptane novel derivative and preparation method thereof of following 1R of general formula or 2S and its application.
In general formula (I) or (I '), R represents hydrogen atom or is expressed as follows the group of formula respectively:
Wherein, R
1Expression contains the alkyl of 1-4 carbon atom, Ar represents phenyl or has the α of one or more identical or different atoms or group-or betanaphthyl arbitrarily that these atoms or group are selected from halogen atom and contain the alkyl of 1-4 carbon atom, the alkoxyl group that contains 1-4 carbon atom or nitro.
Preferred R
1Expression methyl or ethyl, and Ar represents to have arbitrarily the substituent base of one or more methyl or methoxies,
More specifically say R
1The expression methyl, Ar represents phenyl.
According to the present invention, in the formula R respectively the compound of the general formula (I) of expression (II) or (II ') group or (I ') can carry out dihydroxy by the compound of following general formula and obtain:
R in the formula
1Define with Ar such as front.
In general, this dihydroxy by V.VanRheenen etc. at " tetrahedron communication " (Tetrahedron Letters), 23, operation and carrying out under the condition of narration among the 1973-1976 (1976).More specifically say, can be at N-methyl morpholine oxide or triethyl amine oxide or the Tripotassium iron hexacyanide (K
3FeCN
6) exist down, operate and carry out by means of potassium permanganate or perosmic anhydride.In general, in organic-aqueous media, operate, such as in water-trimethyl carbinol or water-acetone, carrying out.
In a general manner, answer the selective oxidation agent so that only form 5 of profile (exo), 6-dihydroxyl.
As shown in the formula preferably and the mineral acid example hydrochloric acid be the same hand shape amine of form of salt and formaldehyde and cyclopentadiene according to S.D.Larsen and P.A.Grieco in " American Chemical Society's will " (J.Amer.Chem.Soc.) 107, operate under the condition of narration among the 1768-1769 (1985), can obtain the product of general formula (III) or (III ') by Diels-Alder (Diels-Alder) reaction.
R in the formula
1Define with Ar such as front.
Same hand shape amine by R shape or S shape is implemented the mixture that present method can cause two kinds of diastereomers, and they reacted in an identical manner in the last dihydroxy reaction stage, will they not separate.
According to the present invention, carry in the presence of the palladium at catalyzer such as charcoal, in the middle of the alcohol of organic solvent such as methyl alcohol and so on, make R in the formula represent the compound of the general formula (I) of general formula (II) or (II ') group or (I ') to carry out hydrogenolysis by means of hydrogen and can obtain that R represents the general formula (I) of hydrogen atom or the compound of (I ') in the formula.
In suitable organic solvent, carry out optionally crystallization of diastereomer with optically active organic acid, from the mixture of general formula (I) and (I ') compound, isolate the 1R isomer that R in the formula represents general formula (I) compound of general formula (II) group.Preferably in fatty alcohol such as Virahol, use the L-dimethoxysuccinic acid.
The novel cpd of general formula (I) is used for preparation especially as U.S. Pat 5,364, the compound of 862 objects, and this is the active medicine of treatment cardiovascular disorder such as hypertension and myocardial ischemia.
Special meaningfully as shown in the formula [1-S-[1 α, 2 β, 3 β, 4 α (S*)]]-4-[7-[[2-(3-chloro-2-thienyl)-1-ethyl diethyldithiocarbamate] amino]-3H-imidazo [4,5-b] pyridin-3-yl]-N-ethyl-2,3-dihydroxyl cyclopentane formamide:
The compound of general formula (I) is used to be prepared as follows the carbon sugar of general formula especially:
In the formula:
R
2The expression carboxyl, alkoxyl group partly contains the carbalkoxy of 1-4 carbon atom, alkoxyl group partly contains N-alkoxy amino carbonyl or the methylol or the alkoxyl-methyl of 1-4 carbon atom, R ' and R " identical or inequality; expression hydrogen atom or contain the aliphatic organic acid residue of 2-4 carbon atom; such as ethanoyl or propionyl; or the residue of aromatic acid such as benzoyl; or R ' and R " form methylene radical together, on its carbon atom, can at random have one or more identical or different substituting groups, these substituting groups are selected from the alkyl that contains 1-4 carbon atom that can form the alicyclic radical that contains 5 or 6 carbon atoms jointly, or phenyl; And G
1Expression hydrogen atom or ammonia official can protecting group G
2More specifically say R
2Expression ethylamino carbonyl or methylol, R ' and R " form isopropylidene together.
The carbon sugar of logical formula V is formed in U.S. Pat 5,364, the structural unit of desired compound in 862.
Can be by the carbon sugar of following method by the logical formula V of compound of general formula (I).
R in the formula can be represented that the hydroxyl protection in general formula (I) compound of hydrogen atom or general formula (II) group becomes ester group or acetal, with obtain as shown in the formula compound:
In the formula: R represents the group of hydrogen atom or general formula (II), R '
1And R "
1Identical or different, expression contains organic aliphatic acid residue such as the ethanoyl or the propionyl of 2-4 carbon atom, or aromatic acid residue such as benzoyl; Perhaps R '
1And R "
1Form a methylene radical together, there are one or more identical or different substituting groups in the area arbitrarily on its carbon atom, and they are selected from the alkyl that contains 1-4 carbon atom that can form the alicyclic radical that contains 5 or 6 carbon atoms jointly, or phenyl.
In general, under the condition of common esterification or acetalation, carry out the protection of hydroxyl, such as at 50 ℃ to the reaction mixture refluxed temperature, by in the presence of tosic acid, in aromatic hydrocarbons organic solvent such as benzene or toluene, react with acetate or propionic acid, along with forming, product separates water outlet; Perhaps in the presence of acid, in aromatic hydrocarbons organic solvent such as benzene or toluene,, under the form of acetal, react in case of necessity with aldehydes or ketones as trifluoroacetic acid.
By hydrogenolysis can wushu in R represent that formula (VI) compound of general formula (II) group changes formula (VI) compound that R in the formula represents hydrogen atom into.
In general, this hydrogenolysis is to carry in the presence of the palladium at catalyzer such as charcoal, and in alcoholic solvent such as methyl alcohol, ethanol or Virahol, under 0-50 ℃ temperature, by hydrogen, the hydrogen with pressurization carries out in case of necessity.
This compound as the general formula (VI) of new compound becomes another object of the present invention.
By with the suitable reactant reaction that can optionally introduce protecting group, R in the formula can be represented that general formula (VI) compound of hydrogen atom changes the compound of following general formula (VII) into:
In the formula: R '
1And R "
1As defined above, G
2The expression amino protecting group.
These blocking groups are selected from those groups that can optionally be removed at last.In particularly suitable blocking group; can list chloracetyl, methoxymethyl, 2; 2; 2-three chloroethoxy bases, the tertiary butyl, benzyl, to nitrobenzyl, to can at random containing a halogen atom on methoxy-benzyl, diphenyl methyl, trialkylsilkl, allyloxy carbonyl, its phenyl ring and contain the alkyl of 1-4 carbon atom or the carbobenzoxy-(Cbz) of the alkoxy substituent of 1-4 carbon atom, or butoxy carbonyl.In other blocking group that is particularly suitable for using, can enumerate by T.W.Greene and P.G.M.Wuts at " blocking group of organizational security in becoming arranged " (Protecting Groups in Organic Synthesis) John Wiley﹠amp; Sons press, 1991 the 2nd edition, the group of being narrated in the 7th chapter.
Tertbutyloxycarbonyl especially meaningfully.
By hydrogenolysis and t-butoxycarbonylating simultaneously, can represent that general formula (VI) compound of general formula (II) group directly obtains G in the formula by R in the formula
2General formula (VII) compound of a tertbutyloxycarbonyl protecting group of expression.
In general, be to carry in the presence of the palladium at catalyzer such as charcoal, allow hydrogen and tert-Butyl dicarbonate react simultaneously with the compound of general formula (VI), operate under 0-50 ℃ the temperature, in as the alcohol organic solvent of methyl alcohol, ethanol or Virahol, carry out.
This compound as the general formula (VII) of new compound becomes another object of the present invention.
The compound of general formula (VII) is oxidized to the compound of following general formula subsequently:
R ' in the formula
1And R "
1And G
2As defined above.
In general, oxidation is to be selected from periodate such as sodium periodate, hypochlorite such as clorox or sodium hypobromite, bromate such as sodium bromate, or existence such as the oxygenant of trimethylamine oxide compound such as N-methylmorpholine oxide compound or triethylamine oxide compound etc. down, by means of rubidium oxide (RuO
4), in case of necessity by its precursor such as RuO
2Or RuCl
3The on-the-spot rubidium oxide that produces realizes that operation is in water, or in water-organic homogeneous phase or heterogeneous medium, as carrying out in water-ethyl acetate mixture.
This oxidizing reaction also can be only by means of clorox (Javel water) or by means of potassium permanganate, or in the presence of oxygenant such as clorox, hydrogen peroxide or alkyl peroxide, carries out by means of sodium wolframate.
Under the described in front condition, R in the formula is represented general formula (VI) compound of hydrogen atom carries out oxidation, also can obtain the compound of general formula (VIII), the nitrogen-atoms of the lactan of the following general formula that will obtain by foregoing protecting group protects then:
R ' in the formula
1And R "
1As defined above.
This compound as the general formula (VIII) of new compound becomes another object of the present invention.
Be suitable for introducing R
2Under the substituent condition, the compound of general formula (VIII) can change the compound of logical formula V into.
Compound by general formula (VIII) and mineral alkali such as sodium hydroxide react, and then replace protecting group G with hydrogen atom
2, or use in case of necessity the hydrogen atom substituent group R '
1And R "
1Just can obtain R
2The compound of the logical formula V of expression carboxyl.
Replace the protecting group G in the compound of general formula (VIII) with hydrogen atom
2, use mineral alkali such as sodium hydroxide effect then, use in case of necessity the hydrogen atom substituent group R '
1And R "
1Can obtain R in the formula
2The compound of the logical formula V of expression carboxyl.
React by compound, and then replace protecting group G with hydrogen atom with alkali metal alcoholates and general formula (VIII)
2, use in case of necessity the hydrogen atom substituent group R '
1And R "
1, can obtain R in the formula
2Represent that its moieties contains the compound of logical formula V of the carbalkoxy of 1-4 carbon atom.
Replace protecting group G in general formula (VIII) compound with hydrogen atom
2, use reaction of alkali metal alkoxide then, use in case of necessity the hydrogen atom substituent group R '
1And R "
1, can obtain R in the formula
2Represent that its moieties contains the compound of logical formula V of the carbalkoxy of 1-4 carbon atom.
Compound reaction by alkylamine and general formula (VIII) replaces protecting group G with hydrogen atom then
2, use in case of necessity the hydrogen atom substituent group R '
1And R "
1, just can obtain R in the formula
2Represent that its moieties contains the compound of logical formula V of the N-alkyl amino-carbonyl of 1-4 carbon atom.
By replace the protecting group G in general formula (VIII) compound with hydrogen atom
2, then with the alkylamine effect, use in case of necessity the hydrogen atom substituent group R '
1And R "
1, can obtain R in the formula
2Represent that its moieties contains the compound of logical formula V of the N-alkyl amino-carbonyl of 1-4 carbon atom.
Compound reaction by with reductive agent such as sodium borohydride or POTASSIUM BOROHYDRIDE and general formula (VIII) replaces protecting group G with hydrogen then
2, use in case of necessity the hydrogen atom substituent group R '
1And R "
1, can obtain R in the formula
2The compound of the logical formula V of expression methylol.
By replace the protecting group G in general formula (VIII) compound with hydrogen atom
2, then with reductive agent such as sodium borohydride or POTASSIUM BOROHYDRIDE reaction, use in case of necessity the hydrogen atom substituent group R '
1And R "
1, can obtain R in the formula
2The compound of the logical formula V of expression methylol.
Can use the compound of logical formula V under the condition described in 862, to obtain the compound of therapeutic activity in U.S. Pat 5,364.
Below each embodiment be used to illustrate the present invention.
Embodiment 1
Be equipped with in the cooling and the 250ml three-necked bottle of stirring system at one, add the α-solution of S-methylbenzylamine (165mmol) in 60ml water of 20g, 36% (w/v) hydrochloric acid by adding 17ml is adjusted to 6.10 with its pH value.Be cooled to after 5 ℃, adding 20ml concentration is the formalin of 37% (w/v).Stirred 5 minutes down at 5 ℃, add 21.8g cyclopentadiene (330mmol) then.Stirred 16 hours down at-5 to 0 ℃.The decant water phase separated is then with the washing of 50ml pentane.Adding the concentrated sodium hydroxide pH value that neutralizes is 8.At this moment, use twice of 70ml ethyl acetate extraction.Add concentrated sodium hydroxide the pH value is transferred to 11, again with twice of 70ml ethyl acetate washing.Merge organic phase,, use dried over sodium sulfate then with 50ml water washing twice.Filter and be evaporated to do after, obtain the 2-(α-S-methyl-benzyl) that 33.1g is faint yellow oily thing-2-azabicyclo [2,2,1] heptan-5-alkene.
Be equipped with in the cooling and the 500ml three-necked bottle of stirring system at one, add 20g 2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptan-solution of 5-alkene (75.34mmol) in the 220ml trimethyl carbinol, under near 25 ℃ temperature, add the solution of 12g N-methylmorpholine oxide compound in 32ml water, add 6.3ml perosmic anhydride (OsO then at leisure
4) 2.5% (w/v) solution in the trimethyl carbinol.Under near 20 ℃ temperature, stirred 2 hours, stirred 3 hours down at 65 ℃ then.Behind the reduction vaporization trimethyl carbinol, residue is dissolved in the 350ml Virahol.Drying under reduced pressure obtains buttery cis-5,6-dihydroxy [2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane after concentrating.Crystallization in hexanaphthene obtains the 5R of 14g, 6S-dihydroxyl-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane, and its isomer purity surpasses 95%.
The NMR (Nuclear Magnetic Resonance) spectrum of measuring in the deuterate chloroform has shown that following chemistry moves (δ): 1.21 (3H, d); 1.38 (1H, d); 1.59 (1H, d); 2.22 (2H, m); 2.45 (1H, dd); 2.95 (1H, s); 3.39 (1H, q); 3.78 (1H, d); 3.90 (1H, d); 7.28 (5H, m).
Embodiment 2
Be equipped with in the cooling and the 500ml three-necked bottle of stirring system at one, the 5R of 18.4g is housed, 6S-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] solution of heptane (76mmol) in 130ml toluene, add 2 of 31.7g, 2-Propanal dimethyl acetal (304mmol) slowly adds 13g trifluoroacetic acid (114mmol) then.Heated 4 hours 10 minutes down at 65 ℃.Be cooled to 30 ℃ and in rotatory evaporator, concentrate remove toluene after, with excessive 2,2-Propanal dimethyl acetal and part trifluoroacetic acid, reaction mixture are dissolved in the methylene dichloride, add the sodium hydroxide neutralization of 100ml 2N then.Decant, with dried over sodium sulfate organic phase, filtration, handling with 30g carbon black discoloring agent under the methylene chloride reflux 30 minutes, filter with Clarcel ert and after drying under reduced pressure concentrates, obtain 18.8g 5R, 6R-isopropylidene dioxy base-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane, its structure warp is confirmed with proton nuclear magnetic resonance spectroscopy in the deuterated chloroform, demonstrates following chemistry and moves (δ): 1.22 (3H, d); 1.23 (6H, s); 1.31 (1H, d); 1.57 (1H, d); 2.08 (1H, d); (2.34 1H, S, broad peak); 2.45 (1H, dd); 3.06 (1H, s); 3.40 (1H, q); 4.09 (1H, d); 4.19 (1H, d); 7.26 (5H, m).
In a 250ml three-necked bottle that stirring system is housed, the charcoal that adds 0.5g 5% (weight) carries the 5R of palladium, 5g, tert-Butyl dicarbonate and the 36ml methyl alcohol of 6S-isopropylidene dioxy base-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane, 3.98g.The equipment argon purge is used hydrogen purge then, places 25 ℃ nitrogen atmosphere at last.Allow then the reaction carried out 5 hours, each quarter with hydrogen purge once, to remove the carbonic acid gas of generation.After concentrating with Clarcel ert filtration and drying under reduced pressure, obtain 4.84g 5R, 6S-isopropylidene dioxy base-2-(tertbutyloxycarbonyl)-2-azabicyclo [2,2,1] heptane, its structure warp is confirmed with proton nuclear magnetic resonance spectroscopy in the deuterated chloroform, demonstrates following chemistry and moves (δ): 1.16 (s, 3H); 1.28 (s, 3H); 1.32 (s, 1H); 1.34 (d, 1H); 1.65 (d, 1H); 2.38 (m, 1H); 2.65 (d, 1H); 2.99 (m, 1H); 3.84 (d, 1H); 3.94 (d, 1H); 4.16 (d, 1H).
In the test tube of a 30ml, add 270mg 5R, the RuO of 6S-isopropylidene dioxy base-2-(tertbutyloxycarbonyl)-2-azabicyclo [2,2,1] heptane (1mmol) and 40mg
2H
2O (0.3 equivalent).Add 10ml ethyl acetate and 720mg water (40 equivalent), add 2.14g sodium periodate (10 equivalent) then and also this test tube is closely sealed.Stirred 16 hours down at 50 ℃.Use the Clarcel filter reaction mixture, use 20ml ethyl acetate washed twice then.Use the dried over sodium sulfate organic phase.Filtering and drying under reduced pressure obtains the solid of 245mg after concentrated, wherein containing 68% 5R, 6S-isopropylidene dioxy base-2-(tertbutyloxycarbonyl)-2-azabicyclo [2,2,1] heptan-3-ketone and 32% starting compound.The structure of products therefrom is confirmed with NMR (Nuclear Magnetic Resonance) spectrum through in dimethyl sulfoxide (DMSO) d6, demonstrates following chemistry and move (δ): 1.38 (9H, s); 1.23 (3H, s); 1.33 (3H, s); 1.85 (1H, d); 1.93 (1H, d); 2.69 (1H, s); 4.24 (1H, s); 4.41 (1H, d); 4.51 (1H, d).
Embodiment 3
Be equipped with in the churned mechanically 25ml autoclave pressure at one, add the 5R of 1.47g, in 6S-isopropylidene dioxy base-2-(tertbutyloxycarbonyl)-2-azabicyclo [2,2, the 1] heptan-solution of 3-ketone in the 10ml dry toluene, add about 0.7ml ethamine then.The closing presure still also heats them 21 hours under 90-100 ℃ temperature.After cooling, steam toluene and use 10ml methylene dichloride and 10ml water dissolution.Behind decant, use 10ml water washing organic phase.Combining water layer 10ml washed with dichloromethane.Merge organic phase and use dried over sodium sulfate then with the washing of 10ml saturated nacl aqueous solution.After filtering and drying under reduced pressure concentrate, obtain the 1.58g product, wherein contain 95% 2R, 3S-isopropylidene dioxy base-4-R-t-butoxycarbonyl amino-1-S-ethylamino carbonyl pentamethylene, its structure is through being confirmed with NMR (Nuclear Magnetic Resonance) spectrum in dimethyl sulfoxide (DMSO) d6, demonstrate following chemistry and move (δ): 0.95 (t, 3H); 1.14 (s, 3H); 1.31 (s, 12H); 1.55 (m, 1H); 2.11 (m, 1H); 2.64 (m, 1H); 3.00 (qi, 2H); 3.77 (m, 1H); 4.23 (m, 1H); 4.54 (m, 1H); 7.07 (d, 1H); 8.12 (t, 1H).
In a 25ml flask, add the 2R of 1.22g, the inferior isopropoxy dioxy of 3S-base-4R-tertbutyloxycarbonyl-1S-ethylamino carbonyl pentamethylene and 10ml methylene dichloride.Under the temperature about 25 ℃, under mechanical stirring, add the 0.85g trifluoroacetic acid.Stir and be concentrated into dried later in 6 hours, obtain 1.16g2R, the inferior isopropoxy dioxy of 3S-base-4R-amino-1S-ethylamino carbonyl pentamethylene trifluoroacetate, its structure is through being confirmed with NMR (Nuclear Magnetic Resonance) spectrum in dimethyl sulfoxide (DMSO) d6, demonstrate following chemistry and move (δ): 0.79 (t, 3H); 1.03 (s, 3H); 1.19 (s, 3H); 1.42 (m, 1H); 2.05 (m, 1H); 2.52 (m, 1H); 2.89 (qi, 2H); 3.04 (m, 1H); 4.16 (m, 1H).
Embodiment 4
Under 5 ℃ to 25 ℃ temperature, 5R with 0.5mmol, 6S-dihydroxyl-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane and 5S, the mixture (mol ratio 78/22) of 6R-dihydroxyl-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane and the solution stirring of 0.5mmol L-dimethoxysuccinic acid in the 1ml Virahol 24 hours.The crystallization that filtering separation obtains is also dry, obtains the 5R of 110mg, 6S-dihydroxyl-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane, enantiomer excessive 97%.
5R, 6S-dihydroxyl-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane and 5S, the mixture (mol ratio 78/22) of 6R-dihydroxyl-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane can obtain by following method:
Be equipped with in the cooling and the 250ml three-necked bottle of stirring system at one, 2-(α-S-methyl-benzyl)-2-azabicyclo [2 of 7g is housed, 2,1] heptan-solution of 5-alkene (35mmol) in the 70ml trimethyl carbinol, under near 25 ℃ temperature, add the solution of 4.12g N-methylmorpholine oxide compound in 11ml water, slowly add 2.5% (w/v) perosmic anhydride (OsO of 360 μ l then
4) solution in the trimethyl carbinol.Under near 20 ℃ temperature, stirred 1 hour, stirred 4 hours down at 65 ℃ then.After decompression steams the trimethyl carbinol, residue is dissolved in the 150ml Virahol.Be evaporated to again do after, obtain the 8.27g product, its structure is shown through proton nuclear magnetic resonance spectroscopy, it is by 5R, 6S-dihydroxyl-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane and 5S, the mixture (mol ratio 78/22) of 6R-dihydroxyl-2-(α-S-methyl-benzyl)-2-azabicyclo [2,2,1] heptane is formed.
Embodiment 5
In a Berghoff (Berghoff) test tube, add 568mg 5R, 70% (weight) aqueous solution of 6S-isopropylidene dioxy base-2-(tertbutyloxycarbonyl)-2-azabicyclo [2,2,1] heptan-3-ketone and 10ml ethamine.Under agitation heated 4 hours down at 60 ℃.Unnecessary ethamine and water are removed in the decompression of cooling back.Behind the drying under reduced pressure, obtain the 2R of 650g, 3S-isopropylidene dioxy base-4R-t-butoxycarbonyl amino-1-S-ethylamino carbonyl pentamethylene, productive rate 98%.Its structure confirms that through proton nuclear magnetic resonance spectroscopy its refractive index is [α]
D 20=15.0 (c=1; Methyl alcohol).
At the 2R of 200mg, in the 3S-isopropylidene dioxy base-4R-t-butoxycarbonyl amino-solution of 1-S-ethylamino carbonyl pentamethylene in the 1.6ml anhydrous methylene chloride, add the trifluoroacetic acid of 275 μ l.Stir under near 5 ℃ temperature and spend the night.Reaction mixture is poured in the 2.5N aqueous sodium hydroxide solution of 4ml.Be lower than concentrating under reduced pressure organic layer under 25 ℃ the temperature.So obtaining the 125mg product is dissolved in the 0.5ml tetrahydrofuran (THF).In this solution, add the 70mg phenylformic acid.After the solution that will obtain is cooled near 0 ℃ temperature, the crystallization that filtering separation obtains, and wash with pentane.So obtain the 2R of 138mg, 3S-isopropylidene dioxy base-4R-amino-1-S-ethylamino carbonyl pentamethylene benzoate.
Embodiment 6
At the 5R that is cooled to 0 ℃ 167mg, in 6S-isopropylidene dioxy base-2-(tert.-butoxy)-2-azabicyclo [2,2, the 1] heptan-solution of 3-ketone in the 1ml methylene dichloride, add 90 μ l trifluoroacetic acids.In 40 minutes, allow temperature rise to 23 ℃, under this temperature, stirred 22 hours then.Again add 90 μ l trifluoroacetic acids, and then stirred 1 hour down at 23 ℃.Behind the reduction vaporization, obtain 123mg5R, in 6S-isopropylidene dioxy base-2-azabicyclo [2,2,1] heptan-3-ketone, near 92%, confirmed its structure with proton nuclear magnetic resonance spectroscopy with its purity of high-performance liquid chromatogram determination.
Under spontaneous pressure, with 10g 5R, 6S-isopropylidene dioxy base-2-azabicyclo [2,2, the 1] heptan-solution of 3-ketone in 70% (weight) aqueous solution of 100ml triethylamine is heated to 110 ℃, kept 20 hours.Unnecessary triethylamine is removed in the decompression of cooling back, uses washed with dichloromethane then, removes unreacted raw material.At this moment concentrate and dry water layer.So obtain 10.54g 2R, 3S-isopropylidene dioxy base-4R-amino-1 S-ethylamino carbonyl pentamethylene.
Claims (18)
1. the 1R of a following general formula or 1S type 2-azabicyclo [2,2,1] heptane derivative:
In the formula, R represents hydrogen atom or is expressed as follows the group of formula respectively:
In the formula, R
1Expression contains the alkyl of 1-4 carbon atom, Ar represents phenyl or has the α of one or more identical or different atoms or group-or betanaphthyl arbitrarily that these atoms or group are selected from halogen atom and contain the alkyl of 1-4 carbon atom, the alkoxyl group that contains 1-4 carbon atom or nitro.
2. according to 2-azabicyclo [2,2,1] heptane derivative, the wherein R of claim 1
1Expression methyl or ethyl, and Ar represents to have arbitrarily the substituent phenyl of one or more methyl or methoxies.
3. according to 2-azabicyclo [2,2,1] heptane derivative, the wherein R of claim 1
1Expression methyl and Ar represents phenyl.
4. claim 1,2 or 3 R represent the preparation method of the compound of general formula (II) or (II ') group, it is characterized in that carrying out the dihydroxy of following formula: compound:
R in the formula
1With Ar such as front claim 1,2 or 3 definition.
5. the method for claim 4 is characterized in that, at N-methylmorpholine oxide compound or triethylamine oxide compound or the Tripotassium iron hexacyanide (K
3FeCN
6) exist down, implement dihydroxy by means of potassium permanganate or perosmic anhydride.
6. the R of claim 1 represents the preparation method of the compound of hydrogen atom, it is characterized in that, catalyzer such as charcoal carry palladium in the presence of, in the organic solvent that is selected from the fatty alcohol that contains 1-3 carbon atom, handle the compound that requires in the claim 1,2 or 3 with hydrogen.
7. represent respectively that by R in the compound of general formula (I) and the formula R that the mixture of general formula (I ') compound of general formula (II) or (II ') group prepares claim 1 represents the method for general formula (I) compound of general formula (II) group, it is characterized in that, in the organic solvent that is selected from the fatty alcohol that contains 1-3 carbon atom, R is represented that general formula (I) compound of general formula (II) group carries out the diastereomer selective crystallization with optics active acid such as L-dimethoxysuccinic acid.
8. the preparation method of the compound of following general formula:
Wherein, R '
1And R "
1Identical or different, expression contains organic aliphatic acid residue such as the ethanoyl or the propionyl of 2-4 carbon atom, or aromatic acid residue such as benzoyl; Perhaps R '
1And R "
1Form a methylene radical together, there are one or more identical or different substituting groups in the area arbitrarily on its carbon atom, and they are selected from the alkyl that contains 1-4 carbon atom that can form the alicyclic radical that contains 5 or 6 carbon atoms jointly, or phenyl, G
2Expression ammonia official energy protecting group the method is characterized in that:
A) under the esterification or acetalation condition of routine, the hydroxyl-functional base of protection claim 1,2 or 3 compound obtains the compound of following general formula
R ' in the formula
1And R "
1Define as the front, R in the claim 1,2 or 3 definition,
B), the compound of general formula (VI) is changed into the compound of following general formula by following method:
R ' in the formula
1And R "
1Define G as the front
2The protecting group of expression nitrogen-atoms,
I) R is represented general formula (VI) the compound hydrogenolysis of general formula (II) group, and with the reagent effect that can introduce nitrogen atom protecting group, hydrogenolysis and protection nitrogen-atoms can carry out simultaneously, perhaps
Ii) with the reagent effect that can represent to introduce on general formula (VI) compound of hydrogen atom nitrogen atom protecting group at R, then
C) making the compound oxidation of general formula (VII) is the compound of general formula (VIII).
9. method according to Claim 8; it is characterized in that; at 50 ℃ to the temperature of reaction mixture refluxed; in the presence of acid; in inert organic solvents, carry out the protection of the hydroxyl in claim 1,2 or 3 the compound by means of the aliphatic acid that contains 2-4 carbon atom or the aldehydes or ketones that is acetal form in case of necessity.
10. method according to Claim 8 is characterized in that, hydrogenolysis is carried in the presence of the palladium at catalyzer such as charcoal and carried out by means of hydrogen, and the protection of nitrogen-atoms is to carry out under the GPF (General Protection False condition of determining according to the character of blocking group.
11. method according to Claim 8 is characterized in that, works as G
2During the expression tertbutyloxycarbonyl, under 0 to 50 ℃ temperature, in the fatty alcohol that contains 1-3 carbon atom, carry in the presence of palladium and the tert-Butyl dicarbonate at catalyzer such as charcoal, hydrogenolysis and protection are carried out in while and H-H reaction simultaneously.
12. method according to Claim 8 is characterized in that, in the presence of oxygenant, by means of the oxide compound (RuO of the rubidium that produces on the spot in case of necessity
4) come the compound of oxidation general formula (VII).
13. the preparation method of the compound of following general formula:
In the formula, R '
1And R "
1And G
2Such as in claim 8 definition, it is characterized in that, under the condition of claim 11,, under the condition of claim 10, the nitrogen-atoms in the lactan that obtains is protected then the compound oxidation of following formula,
R in the formula
1' and R
1" as defined in claim 8, R represents hydrogen atom.
14. the compound of following general formula,
Wherein, R '
1And R "
1Identical or different, expression contains organic aliphatic acid residue such as the ethanoyl or the propionyl of 2-4 carbon atom, or aromatic acid residue such as benzoyl; Perhaps R '
1And R "
1Form a methylene radical together, there are one or more identical or different substituting groups in the area arbitrarily on its carbon atom, and substituting group is selected from the alkyl that contains 1-4 carbon atom that can form the alicyclic radical that contains 5 or 6 carbon atoms together, or phenyl, and G
2Expression ammonia official can protecting group.
15. the compound of following general formula,
Wherein, R represent hydrogen atom or in claim 1,2 or 3 group of defined general formula (II), R '
1And R "
1Identical or different, expression contains organic aliphatic acid residue such as the ethanoyl or the propionyl of 2-4 carbon atom, or aromatic acid residue such as benzoyl; Perhaps R '
1And R "
1Form a methylene radical together, there are one or more identical or different substituting groups in the area arbitrarily on its carbon atom, and substituting group is selected from the alkyl that contains 1-4 carbon atom that can form the alicyclic radical that contains 5 or 6 carbon atoms together, or phenyl.
16. the compound of following general formula,
Wherein, R '
1And R "
1Identical or different, expression contains organic aliphatic acid residue such as the ethanoyl or the propionyl of 2-4 carbon atom, or aromatic acid residue such as benzoyl; Perhaps R '
1And R "
1Form a methylene radical together, there are one or more identical or different substituting groups in the area arbitrarily on its carbon atom, and substituting group is selected from the alkyl that contains 1-4 carbon atom that can form the alicyclic radical that contains 5 or 6 carbon atoms together, or phenyl, and G
2Expression ammonia official can protecting group.
17. the preparation method of following general formula compound,
In the formula, R
2Expression carboxyl, its moieties contain the carbalkoxy of 1-4 carbon atom, and its moieties contains the N-alkyl amino-carbonyl or the alkoxy methyl of 1-4 carbon atom, R '
1And R "
1Identical or different, expression hydrogen atom or contain organic aliphatic acid residue such as the ethanoyl or the propionyl of 2-4 carbon atom, or aromatic acid residue such as benzoyl; Perhaps R '
1And R "
1Form a methylene radical together, there are one or more identical or different substituting groups in the area arbitrarily on its carbon atom, and substituting group is selected from and can forms the alkyl or phenyl that the alicyclic radical that contains 5 or 6 carbon atoms contains 1-4 carbon atom, G together
1Expression hydrogen atom or expression ammonia official can protecting group G
2, the method is characterized in that, according to conceivable R
2The character of group makes the compound reaction of mineral alkali, alkali metal alcoholates, alkylamine or alkali metal borohydride and following general formula, replaces R ' arbitrarily with hydrogen atom then
1And R "
1And protecting group G
2,
In the formula, R '
1And R "
1And G
2Define as the front.
18. the preparation method of following general formula compound,
In the formula, R
2Expression carboxyl, its moieties contain the carbalkoxy of 1-4 carbon atom, and its moieties contains the N-alkyl amino-carbonyl or the alkoxy methyl of 1-4 carbon atom, R '
1And R "
1Identical or different, expression hydrogen atom or contain organic aliphatic acid residue such as the ethanoyl or the propionyl of 2-4 carbon atom, or aromatic acid residue such as benzoyl; Perhaps R '
1And R "
1Form a methylene radical together, there are one or more identical or different substituting groups in the area arbitrarily on its carbon atom, and substituting group is selected from the alkyl that contains 1-4 carbon atom that can form the alicyclic radical that contains 5 or 6 carbon atoms together, or phenyl, G
1Expression hydrogen atom or expression ammonia official can protecting group G
2, the method is characterized in that, replace as shown in the formula the protecting group G in the compound with hydrogen atom earlier
2, then according to the character of conceivable R2 group, make the reaction of mineral alkali, alkali metal alcoholates, alkylamine or alkali metal borohydride and resulting compound, replace R ' arbitrarily with hydrogen atom then
1And R "
1,
R ' wherein
1, R "
1And G
2As defined above.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9506355A FR2720696B3 (en) | 1994-06-02 | 1995-05-30 | Sun curtain device for vehicles. |
| FR95/06355 | 1995-05-30 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB021046816A Division CN1249034C (en) | 1995-05-30 | 2002-02-20 | Novel derivative of 2-azadicyclo-(2,2,1) heptane, its prepn. and use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1185782A true CN1185782A (en) | 1998-06-24 |
| CN1092196C CN1092196C (en) | 2002-10-09 |
Family
ID=9479464
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96194235A Expired - Fee Related CN1092196C (en) | 1995-05-30 | 1996-05-28 | 2-azabicyclo [2,2,1] heptane derivatives, preparation and application thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102185533A (en) * | 2011-05-23 | 2011-09-14 | 北京交通大学 | Stored energy type standard-Z source photovoltaic power generation control system and method |
| US9639106B2 (en) | 2012-03-05 | 2017-05-02 | Solaredge Technologies Ltd. | Direct current link circuit |
| US9647442B2 (en) | 2010-11-09 | 2017-05-09 | Solaredge Technologies Ltd. | Arc detection and prevention in a power generation system |
| US9644993B2 (en) | 2006-12-06 | 2017-05-09 | Solaredge Technologies Ltd. | Monitoring of distributed power harvesting systems using DC power sources |
-
1996
- 1996-05-28 CN CN96194235A patent/CN1092196C/en not_active Expired - Fee Related
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9644993B2 (en) | 2006-12-06 | 2017-05-09 | Solaredge Technologies Ltd. | Monitoring of distributed power harvesting systems using DC power sources |
| US9647442B2 (en) | 2010-11-09 | 2017-05-09 | Solaredge Technologies Ltd. | Arc detection and prevention in a power generation system |
| CN102185533A (en) * | 2011-05-23 | 2011-09-14 | 北京交通大学 | Stored energy type standard-Z source photovoltaic power generation control system and method |
| US9639106B2 (en) | 2012-03-05 | 2017-05-02 | Solaredge Technologies Ltd. | Direct current link circuit |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1092196C (en) | 2002-10-09 |
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