KR970005303B1 - Novel 3-azabicyclo [3.1.1] heptane derivatives and preparation methods thereof - Google Patents

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Description

Novel 3-azabicyclo [3.1.1] heptane Derivatives and Methods for Making the Same

The present invention relates to 3-azabicyclo [3.1.1] heptane derivatives useful for the preparation of quinolone and β-lactam antibacterial agents, and methods for their preparation. The present invention relates to a 3-azabicyclo [3.1.1] heptane derivative and a method for preparing the same that can significantly improve performance.

In general, commercially available quinolone antibacterial agents such as ciprofloxacin, opfloxacin, norfloxacin, exhibit excellent antimicrobial activity against gram-negative bacteria but inferior antimicrobial activity against gram-positive bacteria.

Therefore, the present inventors have studied to solve the problems of the conventional quinolone antibacterial agent, as a result, if it can be used as a side chain of β-lactam antibiotics such as cephalosporin, carbapenem, penem, etc. In particular, when introduced into the side chain of the quinolone antimicrobial agent, the invention has been invented a 3-azabicyclo [3.1.1] heptane derivative and a method for producing the same that exhibits excellent antimicrobial activity and broad antimicrobial spectrum against gram positive bacteria.

An object of the present invention is to provide a 3-azabicyclo [3.1.1] heptane derivative represented by the following general formula (I).

Wherein n is 0 or 1, and R ¹ , R ² , R ³ are each an ordinary amino protecting group such as hydrogen, lower alkyl group, or benzyl or lower alkoxycarbonyl,

R ⁴ represents hydrogen, an unsubstituted or lower alkyl group substituted with a hydroxy key, an amino group, a lower alkoxy key or a halogen.

In the present invention, the lower alkyl group is a straight or branched C ₁ -C ₅ alkyl group including methyl, ethyl, n-propyl, iso-propyl, n-butyl, secondary butyl, iso-butyl, tertiary butyl and the like. Halogen means chlorine, bromine and fluorine. In addition, typical amino protecting groups include t-butoxycarbonyl, ethoxycarbonyl, benzyl group and the like.

The present invention also provides methods for preparing 3-azabicyclo [3.1.1] heptane derivatives. The method of the present invention will be described in detail as follows.

In the above reaction, R ² has the same meaning as described above, and R means methyl, ethyl, t-butyl or isoamyl group.

Method A was prepared by cyclizing the amine of general formula (II) to prepare a compound of general formula (III) (A step; acylating the compound of general formula (III) and then reducing the compound of general formula (IV). (B step), and the compound of formula (IV) is debenzylated (step C) to prepare a compound of formula (I a) of the present invention.

The manufacturing method will be described in more detail as follows.

Compound of formula (II) is heated to 80 ° to 140 ° C. in a solvent such as ethanol, toluene, ethylene glycol monoethyl ether to prepare a compound of formula (III) (step A). The compound of formula III is dissolved in a solvent such as methylene chloride, chloroform, and reacted with acetyl chloride, methyl chloroformate or ethyl chloroformate in the presence of an organic base such as triethylamine, diisopropylamine, pyridine and the like. The resulting compound is dissolved in a solvent such as ethyl ether or tetrahydrofuran (THF) and reduced with a reducing agent such as lithium aluminum hydride (LAH) or borane complex to prepare a compound of formula (IV) (step B). Compound of formula (IV) is debenzylated by hydrocracking reaction in the presence of a catalyst such as palladium with an inorganic acid such as hydrochloric acid, sulfuric acid, or an organic acid such as formic acid or acetic acid to prepare a compound of formula (Ia) of the present invention ( Step C).

Compounds of general formula (II) which are starting materials of Method A are known methods (Pacquet, et al., Heterocycles, 24 (4), 739 (1992) and Allinger et al., J. Org. Chem., 30, The compound of formula (1) obtained by 1945 (1965) was partially decarbonized by heating an inorganic salt such as lithium chloride or sodium chloride with water-dimethylsulfoxide (DMSO) or DMSO solvent at 100 ° to 140 ° C. Compound (2) was prepared (step a), and the compound of formula (2) was dissolved in ethanol or methanol in the presence of a platinum or palladium hydroxide catalyst and hydrogen gas or cyclohexane was added to prepare a compound of formula (3). Step (b) The alcohol of general formula (3) is converted to methanesulfonylchloride or toluenesulfonylchloride in the presence of an organic base such as triethylamine, diisopropylamine, pyridine, or the like without an inert solvent such as methylene chloride, chloroform or solvents. Mesylated or Tosylated After reacting with benzylamine (step C), a compound of formula (II) can be prepared.

Wherein R ² , R ³ and R have the same meaning as described above.

Method B comprises cyclizing a compound of formula (V) to produce a compound of formula (VI) (step A); partially debenzylating, tosylating and reducing the compound of formula (VI) Preparing the compound of (iii) (step D); mesylating or tosylating the compound of the general formula (iv), and then aminating and debenzylating the resulting compound (step E). To prepare the compound of (I b).

The manufacturing method B will be described in more detail as follows.

The compound of formula (V) is treated in a similar manner to step A of method (A) to prepare a compound of formula (VI). Debenzylated a compound of formula (VI) in a similar manner to step C of Method A and methanesulfonyl in the presence of organic bases such as triethylamine, diisopropylamine, pyridine, etc., without an inert solvent or solvent such as methylene chloride, chloroform Tosylated with chloride or toluenesulfonyl chloride and reduced with a reducing agent such as lithium aluminum hydride or borane complex to prepare a compound of formula (VII). The amine of the general formula (I b) of the present invention is prepared by treatment of the alcoholol of general formula (iii) in a similar manner to step C, followed by debenzylation in a similar manner to step C of method A.

Compounds of formula (V), the starting materials of Method B, were prepared by diisobutylaluminum hydride, N-bromosuccinamide, zinc borohydride-chlorotrimethylsilane, sodium sanobo Partially debenzylated in a general manner using a low-hydride-titanium chloride system or the like to prepare a compound of formula (4) (d), and treatment in a similar manner to alcoholol C in formula (4) It can manufacture.

In the above scheme, R ² , R ⁴ and R have the same meaning as described above.

Method C comprises the steps of preparing a compound of formula (VIII) by cyclizing a compound of formula (VII); reducing the compound of formula (VII), protecting the amine group, and then oxidizing (Iii) preparing a compound of formula (iii); preparing a compound of formula (XI) by azizing or rearranging the compound of formula (iii); And N-alkylation of the compound of general formula (XI) followed by deprotection to prepare a compound of general formula (I c) (step I) to prepare an amine of general formula (I c) of the present invention.

The method C will be described in more detail as follows.

The compound of formula (VII) is reduced in a solvent such as methanol, ethanol, ethyl acetate, etc., using a catalyst such as palladium, to prepare an amine. The compound of formula (VII) is prepared by heating (step F). The compound of formula (VII) is reduced with a reducing agent such as lithium aluminum hydride or borane complex, and then amine is protected with di-t-butyldicarbonate according to a general method, and the resulting alcohol compound is converted into dimethylformamide (DMF). ) To pyridinium dichromate (PDC) to prepare a compound of formula (Ⅹ) (G step). The acid is activated by reacting a compound of formula IV in a solvent such as methylene chloride, chloroform, acetone, etc. in the presence of an organic base such as triethylamine, pyridine or diisopropylamine. And reacted with an azide such as sodium azide to produce an acid azide, and then refluxed with alcohols such as t-butanol and ethyl alcohol together with organic bases such as triethylamine and pyridine to form a compound of formula (XI). (Step H). Compounds of general formula (XI) are iodine alkanes of lower alkyl (C ₁ -C ₃ ) and bases such as alkali metal alkoxides or sodium hydrides such as potassium-t-butoxide, sodium ethoxide or sodium hydride in a solvent such as DMF, THF and the like. After the reaction is alkalized, the alkalized product is reacted with a solution such as methanol, ethanol, ethyl acetate, or a super acid such as trichloroacetic acid in a solvent such as methylene chloride or chloroform and then reacted with sodium hydroxide or potassium hydroxide. Neutralization with an inorganic base (step 1) affords a compound of formula (I c) of the present invention.

The starting material of Method C was selected from cyclobutane-1, 1-dicarboxylic acid of general formula (5) by known methods (Schriner, Organic synthesis, John wiley and Sons, New York, 1988, coll. Vol. 6, 271). Step (e) of preparing a compound of formula (6) by chlorination according to the following formula: The compound of formula (6) is stirred under reflux with an alcohol such as methanol, ethanol and thionyl chloride, Step of preparing a compound (step f): heating the compound of formula (7) in a solvent such as acetone, acetonitrile, DMF, DMSO and sodium cyanide, potassium cyanide with potassium iodide at 70 ° to 120 ° C The compound of general formula (VII) can be manufactured through step g).

In the above scheme, R ² and R have the same meaning as described above and R ⁵ means hydrogen or methyl group.

Method D comprises the steps of debenzylating a compound of general formula (XIII), protecting the amine and then oxidizing to produce a compound of general formula (XIII): azide the compound of general formula (XIII) or Amidation and rearrangement to prepare a compound of formula (VII) (step K): N-alkylation of a compound of formula (XIV) followed by deprotection to prepare a compound of formula (Id) L step) to prepare the general formula (Id) of the present invention.

The method D will be described in more detail as follows.

Debenzylated compounds of formula (XII) in a similar manner to step C of method A and protecting the amine groups in solvents such as di-t-butyldicarbonate romethanol, tetradrafurfuran, chloroform Oxidation is carried out in a similar manner as in step to prepare a compound of formula III. Compounds of formula (XIII) are treated in a similar manner to step H of Method C to prepare compounds of formula (XIV). Compounds of formula (XIV) are treated in a similar manner to step 1 of Method C to produce N-alkylated acetates, which are treated with sodium methoxide in methanol or reacted in a methanol solution of potassium hydroxide to prepare alcohols. In the solvent, such as alcoholol DMSO, DMF, THF, and the like, a base such as sodium hydride and iodine of a lower alkyl group (C ₁ -C ₃ ) are reacted at an alkanol at -10 to 10 ° C to prepare an alkylated compound. Deprotection is carried out in a similar manner as used in step I of process C to prepare compounds of formula (I d) of the present invention.

Compound (XII), the starting material of Method D, reduced the compound of Formula (VI) produced in Method B by a similar method used in Step B of Method A to prepare a compound of Formula (8) (step h). The compound of formula (8) is reacted at -10 ° C to 25 ° C with acetic anhydride or acetyl chloride in the presence of organic bases such as triethylamine, pyridine and diisopropylamine in a solvent such as methylene chloride or chloroform. Prepare compound of XII) (step i).

Wherein R ² has the same meaning as described above.

Method E was prepared by treating a compound of formula (XII) with potassium hydroxide and methanol to deprotect the acetoxy group with a hydroxyl group to produce an alcohol of formula (XV) (step M). A compound of the general formula (XIV) is prepared by amination with R ² NH ₂ in a similar manner as in step. Compound (I e) of the present invention is prepared by treating a compound of Formula (VI) in a similar manner to step C of Method A.

In the above scheme, R ¹ , R ² , R ³ and n have the same meanings as described above, and R ⁶ means halogen or R ² R ³ N, such as a fluorine atom, a chlorine atom or a bromine atom.

Method F is prepared by 1) halogenating a compound of general formula (X ') to prepare a compound of general formula (I f) of the present invention in which halogen is substituted, or 2) using a compound of general formula (X') Amination is carried out in a similar manner to prepare compounds of formula (I f) of the present invention. In addition, mesylated or tosylated compounds of general formula (X) are reacted with halogenated compounds of alkali metals such as lithium chloride and lithium bromide at 10 ° to 100 ° C. in DMF, DMSO, methylene chloride or chloroform solvents. Treatment of a compound of formula (XVII) with a fluorination reagent such as dialkylaminosulfurtrifluoride such as N, N-dimethylaminosulfurtrifluoride in a haloalkane solvent such as methylene chloride at -10 ° C to 20 ° C To prepare a compound of formula (I f).

Hereinafter, the present invention will be described in more detail with reference to Examples, and the following Examples illustrate the present invention and do not limit the present invention.

Example 1

Preparation of 1-aminomethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of Isoamyl 7-phenyl-6, 8-dioxaspiro [3.5] nonan-2-carboxylate

Diisoamyl 7-phenyl-6, 8-dioxaspiro [3.5] nonane-2,2-dicarboxylate 8. 8 gr and lithium chloride 3. 13 gr was added to a mixed solvent of 0.65 ml of water and 65 ml of DMSO. And reflux for 8 hours. The reaction mixture is poured into 100 ml of water and extracted twice with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and then silica gel column chromatography (hexane (hereinafter n-Hex): ethyl acetate (hereinafter EA) = 10: 1) was used to obtain the target compound 5. 1 g (yield 83%). Get

Elemental Analysis for C ₁₉ H ₂₆ O ₄ :

Calculated Value (%): C; 71.70, H; 8.18

Found (%): C; 72.41, H; 8.91

2) Preparation of Isoamyl 3, 37-dihydroxymethylcyclobutane-1-carboxylate

5.74 gr of isoamyl 7-phenyl-6,8-dioxaspiro [3,5] nonane-2-carboxylate and 1.10 gr of palladium hydroxide obtained in 1) were added to 60 ml of cyclohexene and 140 ml of ethanol for 10 hours. Reflux for a while. The reaction solution is filtered through celite and the filtrate is evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-Hex: EA = 1: 1) to obtain 3.81 gr (yield 90%) of the title compound.

Elemental Analysis for C ₁₂ H ₂₂ O ₄ :

Calculated Value (%): C; 62.6, H; 19.57

Found (%): C; 61.4, H; 39.18

3) Preparation of N, N'-dibenzyl-2-oxo-5-aminomethyl-3-azabicyclo [3.1.1] heptane

4.76 gr of isoamyl 3,4-dihydroxymethylcyclobutane-1-carboxylate and 2.5 gr of triethylamine were dissolved in 80 ml of methylene chloride. The solution was cooled to 0 ° C., and then slowly added dropwise to 3.42 gr of methanesulfonyl chloride. do. After stirring the reaction solution at 0 ° C. for 4 hours, the reaction solution was washed with water, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The residue is taken up in 50 ml of ethanol, 4.48 gr of benzylamine are added and stirred at room temperature for 14 hours. The reaction solution was slowly heated to reflux for 10 hours, and then silica gel tube chromatography (chloroform: methanol = 10: 1) obtained by evaporating the solvent under reduced pressure to obtain 3.90 gr (yield 60%) of the title compound.

Calculated Value (%): C; 78.75, H; 7.50, N; 8.75

Found (%): C; 78.13, H; 7.82, N; 9.42

4) Preparation of N, N'-dibenzyl-1aminomethyl-3-azabicyclo [3.1.1] heptane

N, N'-dibenzyl-2-oxo-5-aminomethyl-3-azabicyclo [3.1.1] heptane 3.20 gr 10 mL THF in a reaction flask suspended from LAH 0.38 gr in 10 mL THF. The solution dissolved in was slowly added dropwise at 0 ° C. After the dropwise addition, the reaction solution was refluxed for 4 hours, cooled to room temperature and 1 ml of water was added thereto. The mixture was stirred well for 2 hours, and 3 ml of 6N hydrochloric acid was added, followed by further stirring for 1 hour, followed by filtration under reduced pressure. The filtrate was evaporated under reduced pressure, the residue was dissolved in water, neutralized with 15% aqueous potassium hydroxide solution and extracted three times with ethyl ether. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and silica gel column chromatography (chloroform: methanol = 10: 1) gave 2.76 gr (yield 90%) of the title compound.

Elemental Analysis for C ₂₁ H ₂₆ N ₂ :

Calculated Value (%): C; 82.35, H; 8.50, N; 9.15

Found (%): C; 81.72, H; 8.12, N; 9.61

5) Preparation of 1-aminomethyl-3-azabicyclo [3.1.1] heptane

3.06 gr of N, N'-dibenzyl-1-aminomethyl-3-azabicyclo [3.1.1] heptane are dissolved in 20 ml of methanol containing 1 ml of formic acid, and suspended in 10% pd / c 0.5 gr. Debenzyl (initial hydrogen pressure 65 psi). The reaction solution is filtered through celite and the solid cake is washed with methanol and water in that order. The combined filtrate and washings were evaporated under reduced pressure, and the residue was dissolved in 10 ml of water and extracted twice with EA (2 × 10 ml). The aqueous solution is saturated with potassium hydroxide and extracted five times (5 × 10 mL) with ethyl ether. The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure to obtain 1.18 gr (yield 94%) of the title compound.

Elemental Analysis for C ₇ H ₁₄ N ₂ :

Calculated Value (%): C; 66.67, H; 11.11, N; 22.22

Found (%): C; 66.21, H; 11.41, N; 22.91

Example 2

Preparation of 1- (N-methyl) aminomethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1- (N-benzyl-N-methyl) aminomethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane

A solution of 3.2 gr of 5- (N-benzyl) aminomethyl-2-oxo-3- (N-benzyl) azabicyclo [3.1.1] heptane and 1.21 gr of triethylamine in 30 ml of methylene chloride was cooled to 0 ° C. 2 ml of ethylchloroformate is added dropwise. After the reaction mixture was stirred for 2 more hours at room temperature, the reaction mixture was washed twice with water, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The solution in which the residue was dissolved in 30 mL of THF was added dropwise while stirring to a suspension suspended at 0 ° C. and 0.76 gr of LAH in 20 mL of THF. The reaction mixture was stirred at reflux for 4 hours, the reaction temperature was cooled to room temperature, 3 ml of water was added thereto, and vigorously stirred for 1 hour. The reaction mixture was filtered under reduced pressure, and the solvent was evaporated under reduced pressure, followed by silica gel column chromatography (n-Hex: EA = 1: 2) to obtain 2.69 gr (yield 84%) of the title compound.

Elemental Analysis for C ₂₂ H ₂₈ N ₂ :

Calculated Value (%): C; 82.50, H; 8.75, N; 8.75

Found (%): C; 82.11, H; 8.71, N; 8.91

2) Preparation of 1- (N-methyl) aminomethyl-3-azabicyclo [3.1.1] heptane

Dissolve 2.4 gr of 1- (N-benzyl-N-methyl) aminomethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane in 30 ml of methanol and suspend 10% pd / c 0.24 gr before formic acid 1 ㎖ was added, and debenzyl (hydrogen initial pressure 65 psi) with hydrogen was treated in the same manner as in Example 1-5 to obtain 0.88 gr (yield 90%) of the title compound.

Elemental Analysis for C ₈ H ₁₆ N ₂ :

Calculated Value (%): C; 68.57, H; 11.43, N; 20.00

Found (%): C; 68.10, H; 11.11, N; 19.81

Example 3

Preparation of 1- (N-ethyl) aminomethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1- (N-ethyl-N-benzyl) aminomethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane

3.2 gr of 5- (N-benzyl) aminomethyl-2-oxo-3- (N-benzyl) azabicyclo [3.1.1] heptane were added to a solution of 30 ml of methylene chloride and 10 ml of acetic anhydride and stirred at room temperature for 1 hour. After stirring, reflux for 1 hour. The reaction mixture was cooled, poured into 100 mL of ice-water, the organic layer was separated, washed twice with saturated aqueous sodium bicarbonate and dried over anhydrous magnesium sulfate. The residue obtained by evaporating the dried organic layer under reduced pressure was reduced to LAH in the same manner as in 1) of Example 2 to obtain the title compound 2.54 gr (yield 76%).

Elemental Analysis for C ₂₃ H ₃ ON ₂ :

Calculated Value (%): C; 82.63, H; 8.98, N; 8.38

Found (%): C; 82.12, H; 9.21, N; 8.61

2) Preparation of 1- (N-ethyl) aminomethyl-3-azabicyclo [3.1.1] heptane

1- (N-ethyl-N-benzyl) aminomethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane 2. 50 gr was treated in the same manner as in Example 2 2) to give the title compound 1. 03 gr (yield 96%) were obtained.

Elemental Analysis for C ₉ H ₁₈ N ₂ :

Calculated Value (%): C; 70.13, H; 11.69, N; 18.18

Found (%): C; 70.62, H; 12.01, N; 18.90

Example 4

Preparation of 1-amino-3-azabicyclo [3.1.1] heptane

1) Preparation of 3-chlorocyclobutane-1, 1-dicarboxylic acid

50 gr of cyclobutane-1 and 1-dicarboxylic acid were added to 450 ml of benzene, and 29.5 ml of sulfuryl chloride and 1.2 gr of benzoyl peroxide were added slowly and stirred under reflux while heating and stirring. The solvent was evaporated under reduced pressure to give a white solid having a target compound and starting material of 2: 1.

Mass spectrometry: 179 (M ⁺ ), 181 (M ⁺ +2)

2) Preparation of Dimethyl 3-chlorocyclobutane-1, 1-dicarboxylate

30 gr of the mixture of 1) above is suspended in 150 ml of methanol, 30 ml of thionyl chloride is added, and the mixture is stirred under reflux for 5 hours. The reaction solution was evaporated under reduced pressure and silica gel column chromatography (n-Hex: EA = 10: 1) gave 18.5 gr (yield 80%) of the title compound.

Elemental Analysis for C ₈ H ₁₁ O ₄ CI:

Calculated Value (%): C; 54.82, H; 5.33

Found (%): C; 55.11, H; 5.42

3) Preparation of Dimethyl 3-cyanocyclobutane-1, 1-dicarboxylate

10.3 gr of dimethyl 3-chlorocyclobutane-1, 1-dicarboxylate, 9.9 gr of potassium iodide and 3.6 grN of potassium cyanide are poured into 100 ml of DMF and extracted twice with EA (2 × 100 ml). The extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure, followed by silica gel column chromatography (n-Hex: EA = 5: 1) to obtain 7.31 gr (yield 74%) of the title compound.

Elemental Analysis for C ₉ H ₁₁ O ₄ N:

Calculated Value (%): C; 54.82, H; 5.58, N; 7.10

Found (%): C; 54.26, H; 5.91, N; 7.14

4) Preparation of 1-methoxycarbonyl-2-oxo-3-azabicyclo [3.1.1] heptane

To a solution of 6.6 gr of dimethyl 3-cyanocyclobutane-1 and 1-diclocarboxylate in 50 ml of methanol was added 10 gr of a 50% Rennie nickel water suspension and stirred for 6 hours while injecting hydrogen. The catalyst is filtered off through celite and the solvent is evaporated under reduced pressure. The residue is taken up in 50 ml of toluene and stirred under reflux for 8 hours. The reaction solvent was evaporated under reduced pressure and silica gel column chromatography (n-Hex: EA = 1: 2) gave 4.02 gr (yield 71%) of the title compound.

Elemental Analysis for C ₈ H ₁₁ NO ₃ :

Calculated Value (%): C; 56.80, H; 6.51, N; 8.28

Found (%): C; 57.12, H; 6.71, N; 8.41

5) Preparation of 1-hydroxymethyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

To a suspension of 0.82 gr of LAH suspended in 20 ml of THF, a solution of 16.9 gr of 1-methoxycarbonyl-2-oxo-3-azabicyclo [3.1.1] heptane in 80 ml of THF was slowly added dropwise at 0 ° C. After stirring for 8 hours at room temperature and refluxing for 1 hour, the mixture was cooled in an ice bath, and 20 ml of water was added dropwise with vigorous stirring, and the mixture was further stirred for 1 hour. The mixture is filtered and 21.8 gr of di-t-butyl dicarbonate is added to the filtrate and stirred at 60 ° C. for 5 hours. The solvent was evaporated under reduced pressure, and silica gel tube chromatography (n-Hex: EA = 1: 1) yielded 13.6 gr (yield 61%) of the title compound.

Elemental Analysis for C ₁₂ H ₂₁ NO ₃ :

Calculated Value (%): C; 63.44, H; 9.25, N; 6.17

Found (%): C; 64.01, H; 9.42, N; 6.45

6) Preparation of 1-carboxy-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

11.2 gr of 1-hydroxymethyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane is added to a 50 ml solution of DMF containing 18.8 gr of PDC and stirred at 60 ° C. for 3 hours. The reaction solution is poured into water and stirred, the resulting solid is filtered off, washed well with water and dried under reduced pressure. Recrystallization with ethyl ether-ethanol gave the title compound 7.25 gr (yield 61%).

Elemental Analysis for C ₁₂ H ₁₉ NO ₄ :

Calculated Value (%): C; 59.75, H; 7.88, N; 5.81

Found (%): C; 60.12, H; 7.67, N; 5.60

7) Preparation of N, N'-di-t-butoxycarbonyl-1-amino-3-azabicyclo [3.1.1] heptane

8.11 gr of 1-carboxy-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane and 4.5 ml of triethylamine are added to 50 ml of acetone and stirred for 5 minutes. The reaction solution was cooled to 0 ° C., 3.2 ml of ethyl chloroformate was diluted in 10 ml of acetone, and slowly added dropwise. After stirring for 20 minutes, a solution of 3.8 gr of sodium azide in 20 ml of water was added dropwise at the same temperature for 30 minutes. Stir. The reaction solution was poured into 200 ml of ice-water, extracted three times with toluene (3 × 70 ml), dried over anhydrous magnesium sulfate, filtered, and the filtrate was stirred under reflux for 1 hour. Toluene was evaporated under reduced pressure, 10 ml of t-butanol and 3.4 ml of triethylamine were added, followed by stirring under reflux for about 3 hours, and the reaction solution was concentrated under reduced pressure. 20 ml of water was added to the mixture and extracted with methylene chloride three times (3 × 15 ml), dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and silica gel column chromatography (n-Hex: EA = 5: 1) Compound 4.30 gr was obtained.

Elemental Analysis for C ₁₆ H ₂₈ N ₂ O ₄ :

Calculated Value (%): C; 61.54, H; 8.97, N; 8.97

Found (%): C; 61.93, H; 9.21, N; 9.10

8) Preparation of 1-amino-3-azabicyclo [3.1.1] heptane

3.12 gr of N, N'-di-t-butoxycarbonyl-1-amino-3-azabicyclo [3.1.1] heptane was dissolved in 20 ml of methanol saturated with hydrogen chloride and stirred at room temperature for 5 hours, Methanol was evaporated under reduced pressure, ethyl ether was solidified, the solid was filtered, dissolved in 3 ml of saturated aqueous sodium hydroxide solution, extracted with ethyl ether (5 ml × 5), and the extract was dried over anhydrous magnesium sulfate. The extract was evaporated under reduced pressure to remove the solvent to obtain 1.03 gr (yield 92%) of the title compound.

Elemental Analysis for C ₁₆ H ₁₂ N ₂ :

Calculated Value (%): C; 64.29, H; 10.71, N; 25.00

Found (%): C; 63.31, H; 11.68, N; 24.19

Example 5

Preparation of 1- (N-ethyl) amino-3-azabicyclo [3.1.1] heptane

1) Preparation of 1- (N-ethyl-N-t-butoxycarbonyl) amino-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

A solution of 4.3 gr of 60% sodium hydride dissolved in 10 ml of DMF was added dropwise. After the reaction solution was stirred at room temperature for 2 hours, a solution of 1.8 g of iodine iodide dissolved in 15 ml of DMF was added dropwise and stirred for 3 hours. The reaction mixture was extracted with 50 ml of water twice (2 × 50 ml) with solso EA, and then silica gel tube chromatography (n-Hex: EA = 5: 1) gave 2.8 gr (yield 82%) of the title compound.

Elemental Analysis for C ₁₈ H ₃₂ N ₂ O ₄ :

Calculated Value (%): C; 63.53, H; 9.41, N; 8.24

Found (%): C; 63.61, H; 9.72, N; 8.36

2) Preparation of 1- (N-ethyl) amino-3-azabicyclo [3.1.1] heptane

2.55 gr of 1- (N-ethyl-Nt-butoxycarbonyl) -3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane was treated in the same manner as in Example 4, 8) to give the target compound. 1.00 gr (yield: 96%) were obtained.

Elemental Analysis for C ₈ H ₁₆ N ₂ :

Calculated Value (%): C; 68.57, H; 11.43, N; 20.00

Found (%): C; 69.28, H; 12.11, N; 20.87

Example 6

Preparation of 1- (N-methyl) amino-3-azabicyclo [3.1.1] heptane

Treatment was carried out in the same manner as in Example 5 1) and 2) using 3.12 gr of N, N'-di-butoxycarbonyl-1-amino-3-azabicyclo [3.1.1] heptane and 1.56 gr of iodide methane To obtain the target compound, 1.01 gr (yield 80%).

Elemental Analysis for C ₇ H ₁₄ N ₂ :

Calculated Value (%): C; 66.67, H; 11.11, N; 22.22

Found (%): C; 66.01, H; 11.96, N; 23.10

Example 7

Preparation of 1-aminomethyl-5-methyl-3-azabicycle [3.1.1] heptane

1) Preparation of Diisoamyl 3-benzyloxymethyl-3-hydroxymethylcyclobutane-1, 1-dicarboxylate

21.6 gr of diisoamyl 7-phenyl-6, 8-dioxaspiro [3, 5] nonane-2, 2-dicarboxylate are dissolved in 200 ml of methylene chloride, cooled to 0 ° C. and 70% diisobutyl with stirring 50 ml of aluminum hydride is diluted in 50 ml of methylene chloride and added dropwise, followed by stirring for 2 hours. 20 ml of cold water is added to the reaction mixture, the organic layer is separated, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (n-Hex: EA = 3: 1) to obtain 19.44 gr (yield 90%) of the title compound.

Elemental Analysis for C ₂₅ H ₃₈ O ₆ :

Calculated Value (%): C; 69.12, H; 8.76

Found (%): C; 69.47, H; 8.97

2) Preparation of 1-isoamyloxycarbonyl-2-oxo-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane

Diisoamyl 3-hydroxymethyl-3-benzyloxymethylcyclobutane-1 and 10.8 gr of 1-dicarboxylate were treated in the same manner as in Example 3, 3, to obtain 7.67 gr (yield 71%) of the target compound. Got it.

Elemental Analysis for C ₂₇ H ₃₃ NO ₄ :

Calculated Value (%): C; 74.48, H; 7.59, N; 3.22

Found (%): C; 73.97, H; 7.71, N; 3.36

3) Preparation of 1-hydroxymethyl-5-methyl- (N-benzyl) azabicyclo [3.1.1] heptane

4.34 gr of 1-isoamyloxycarbonyl-2-oxo-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane was dissolved in 40 ml of methanol and suspended in 10% Pd / C 1gr. Then 5 ml of concentrated hydrochloric acid is added and hydrogenated (initial hydrogen pressure 60 psi). The reaction solution was filtered through Celite, the solvent was evaporated under reduced pressure, 1.70 gr of toluene sulfonyl chloride and 1.21 gr of triethylamine were added to 30 ml of methylene chloride, and the mixture was stirred under reflux for 10 hours. The reaction mixture is washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The solution of the residue dissolved in 30 ml of THF was added dropwise to a suspension solution of 1.43 gr of LAH suspended in 10 ml of THF, followed by stirring for 1 hour and refluxed for 30 minutes. The reaction mixture was cooled, 10 ml of water was added thereto, vigorously stirred for 1 hour, and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (n-Hex: EA = 1: 1) to obtain 1.32 gr (yield 60%) of the title compound.

Elemental Analysis for C ₁₅ H ₂₁ NO:

Calculated Value (%): C; 77.92, H; 9.09, N; 6.06

Found (%): C; 78.13, H; 9.21, N; 6.31

4) Preparation of 1-aminomethyl-5-methyl-3- (N-benzyl) azabicyclo [3.1.1] heptane

4.38 gr of 1-hydroxy-5-methyl-3- (N-benzyl) azabicyclo [3.1.1] heptane and 2.5 gr of triethylamine were added to 50 ml of methylene chloride and cooled to 0 ° C., followed by methanesulfonyl chloride. 2 ml is added dropwise and stirred for 3 hours. The reaction solution was washed with water, the solvent was evaporated under reduced pressure, and then poured into 100 ml of 30% ammonia water and stirred at room temperature for 10 hours. Concentrate under reduced pressure until the volume of the reaction solution is half, add 10 ml of concentrated hydrochloric acid, and then evaporate the water under reduced pressure. The residue is taken up in 5 ml of water, saturated with caustic soda and extracted five times (5 × 10 ml) with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure at low temperature to obtain 1.74 gr (yield 81%) of the title compound.

Elemental Analysis for C ₁₅ H ₂₂ N ₂ :

Calculated Value (%): C; 78.26, H; 9.57, N; 12.17

Found (%): C; 78.71, H; 9.31, N; 12.46

5) Preparation of 1-aminomethyl-5-methyl-3-azabicyclo [3.1.1] heptane

2.18 gr of 1-aminomethyl-5-methyl-3- (N-benzyl) azabicyclo [3.1.1] heptane was treated in the same manner as in Example 5) to obtain 1.05 gr (yield 90%) of the title compound. .

Elemental Analysis for C ₈ H ₁₆ N ₂ :

Calculated Value (%): C; 68.57, H; 11.43, N; 20.00

Found (%): C; 69.06, H; 11.71, N; 20.81

Example 8

Preparation of 1- (N-methyl) aminomethyl-5-methyl-3-azabicyclo [3.1.1] heptane

3), 4) and 5) of Example 7 using 2.19 gr of 1-hydroxymethyl-5-methyl-3- (N-benzyl) azabicyclo [3.1.1] heptane and 50 ml of 40% aqueous methylamine solution Treated in the same manner as in to obtain 0.97 gr (yield 69%) of the title compound.

Elemental Analysis for C ₉ H ₁₈ N ₂ :

Calculated Value (%): C; 70.13, H; 11.09, N; 18.18

Found (%): C; 71.01, H; 11.91, N; 18.76

Example 9

Preparation of 1- (N-ethyl) aminomethyl-5-methyl-3-azabicyclo [3.1.1] heptane

3), 4) and 5) of Example 7 using 2.19 gr of 1-hydroxymethyl-5-methyl-3- (N-benzyl) azabicyclo [3.1.1] heptane and 20 ml of 70% ethylamine Treatment in the same manner gave 1.03 gr (yield 61%) of the title compound.

Elemental Analysis for C ₁₀ H ₂₀ N ₂ :

Calculated Value (%): C; 70.43, H; 11.90, N; 16.67

Found (%): C; 72.21, H; 11.36, N; 17.41

Example 10

Preparation of 1-amino-5-methyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1-carboxy-5-methyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

Dissolve 21.9 gr of 1-carboxy-5-methyl-3- (N-benzyl) azabicyclo [3.1.1] heptane and 10.9 gr of di-t-butyldicarbonate in 300 ml of methanol and suspend 10% Pd / C 5 gr. Hydrogenated (initial hydrogen pressure 65 psi). The reaction solution was filtered through celite, the solvent was evaporated under reduced pressure, and the residue was dissolved in 50 mL of DMF, added to 100 mL of DMF solution containing 20 gr of PDC, and stirred at 60 ° C. for 3 hours. The reaction solution was treated in the same manner as in 6) of Example 4 to obtain 16.3 gr (yield 65%) of the title compound.

Elemental Analysis for C ₁₃ H ₂₁ NO:

Calculated Value (%): C; 61.18, H; 8.24, N; 5.49

Found (%): C; 61.91, H; 8.46, N; 6.02

2) Preparation of N, N'-di-t-butoxycarbonyl-1-amino-5-methyl-3-azabicyclo [3.1.1] heptane

Treatment with 1-carboxy-5-methyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane in the same manner as in Example 4, 7) to give the title compound 6.91 gr (yield) 53%).

Elemental Analysis for C ₁₇ H ₃₀ N ₂ O ₄ :

Calculated Value (%): C; 62.58, H; 9.20, N; 8.59

Found (%): C; 63.10, H; 9.31, N; 9.12

3) Preparation of 1-amino-5-methyl-3-azabicyclo [3.1.1] heptane

3.26 gr of N, N'-di-t-butoxycarbonyl-1-amino-5-methyl-3-azabicyclo [3.1.1] heptane was treated in the same manner as in 8) of Example 4 to give the title compound 1.14 gr (yield 90%) was obtained.

Elemental Analysis for C ₇ H ₁₄ N ₂ :

Calculated Value (%): C; 66.67, H; 11.11, N; 22.22

Found (%): C; 67.41, H; 11.54, N; 23.01

Example 11

Preparation of 1- (N-ethyl) amino-5-methyl-3-azabicyclo [3.1.1] heptane

3.26 gr of N, N'-di-t-butoxycarbonyl-1-amino-5-methyl-3-azabicyclo [3.1.1] heptane was treated in the same manner as in Example 5 to obtain 1.02 gr of the target compound (yield) 71%).

Elemental Analysis for C ₉ H ₁₈ N ₂ :

Calculated Value (%): C; 70.13, H; 11.69, N; 18.18

Found (%): C; 70.72, H; 12.21, N; 18.91

Example 12

Preparation of 1- (N-methyl) amino-5-methyl-3-azabicyclo [3.1.1] heptane

3.26 gr of N, N'-di-t-butoxycarbonyl-1-amino-5-methyl-3-azabicyclo [3.1.1] heptane was treated in the same manner as in Example 6 to yield 1.13 gr of the target compound (yield) 76%).

Elemental Analysis for C ₈ H ₁₆ N ₂ :

Calculated Value (%): C; 68.57, H; 11.43, N; 20.00

Found (%): C; 69.21, H; 12.01, N; 20.91

Example 13

Preparation of 1-amino-5-hydroxymethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1-benzyloxymethyl-5-acetoxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane

1-Isoamyloxycarbonyl-2-oxo-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane 43.4 gr was treated in the same manner as in Example 4, 5) to obtain impure 1 Hydroxymethyl-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane 26 gr which was obtained in 100 ml of methylene chloride containing 50 ml of acetic anhydride and 30 ml of triethylamine. Dissolve in solution and stir at room temperature for 3 hours. The reaction mixture was washed with 100 ml of water, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and silica gel tube chromatography (n-Hex: EA = 5: 1) gave the target compound 26.42 gr (yield 72%).

Elemental Analysis for C ₂₄ H ₂₉ NO ₃ :

Calculated Value (%): C; 75.99, H; 7.65, N; 3.69

Found (%): C; 76.41, H; 8.02, N; 4.14

2) Preparation of 1-hydroxymethyl-5-acetoxymethyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

18.35 gr of 1-benzyloxymethyl-5-acetoxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane and 11 gr of di-t-butyldicarbonate were dissolved in 400 ml of methanol and 10% Pd / Suspend and hydrogenate C 5 gr (initial hydrogen pressure 65 psi). The reaction solution was filtered through celite, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-Hex: EA = 1: 1) to obtain 12.54 gr (yield 88%) of the title compound.

Elemental Analysis for C ₁₅ H ₂₅ NO ₅ :

Calculated Value (%): C; 60.20, H; 8.36, N; 4.68

Found (%): C; 60.71, H; 8.91, N; 5.10

3) Preparation of 1- (N-tbutoxycarbonyl) amino-5-acetoxymethyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

14.3 gr of 1-hydroxymethyl-5-acetoxymethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane was treated in the same manner as in Example 4 6) and 7) to give the desired compound. 25.6 gr (yield 67%) was obtained.

Elemental Analysis for C ₁₉ H ₃₂ N ₂ O ₆ :

Calculated Value (%): C; 59.38, H; 8.33, N; 7.30

Found (%): C; 61.20, H; 8.34, N; 7.81

4) Preparation of 1-amino-5-hydroxymethyl-3-azabicyclo [3.1.1] heptane

3.82 gr of 1- (Nt-butoxycarbonyl) amino-5-acetoxymethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane was dissolved in 20 ml of methanol saturated with hydrogen chloride gas and room temperature Stir for 4 hours. The reaction mixture was evaporated under reduced pressure, dissolved in 10 ml of water and extracted twice with EA (2 × 10 ml). The aqueous layer was evaporated under reduced pressure, dissolved in 20 ml of methanol, 1.2 gr of sodium methoxide was added, and the mixture was stirred at room temperature for 1 hour. The solvent is evaporated again under reduced pressure, dissolved in 10 ml of water and neutralized with 10% HCl. The aqueous layer was saturated with salt, extracted five times with ethyl ether (5 × 10 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to yield 1.13 gr (yield 81%) of the title compound.

Elemental Analysis for C ₇ H ₁₄ N ₂ O:

Calculated Value (%): C; 59.15, H; 9.86, N; 19.72

Found (%): C; 60.78, H; 9.41, N; 18.41

Example 14

Preparation of 1-amino-5-methoxymethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1- (N-t-butoxycarbonyl) amino-5-methoxymethyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

3.67 gr of 1- (Nt-butoxycarbonyl) amino-5-acetoxymethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane and 0.52 gr of sodium methoxide were added to 20 ml of methanol. After stirring for 1 hour at room temperature, 1.42 gr of methane iodide was added, followed by further stirring for 4 hours.

The reaction solution was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-Hex: EA = 2: 1) to obtain 2.68 gr (yield 79%) of the title compound.

Elemental Analysis for C ₁₈ H ₃₂ N ₂ O ₅ :

Calculated Value (%): C; 60.67, H; 8.99, N; 7.87

Found (%): C; 60.13, H; 9.41, N; 8.46

2) Preparation of 1-amino-5-methoxymethyl-3-azabicyclo [3.1.1] heptane

1- (Nt-butoxycarbonyl) amino-5-methoxymethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane 2.54 gr was treated in the same manner as in Example 6 to give the target compound. 1.06 gr (yield 90%) was obtained.

Elemental Analysis for C ₈ H ₁₆ N ₂ O:

Calculated Value (%): C; 61.54, H; 10.26, N; 17.95

Found (%): C; 60.72, H; 10.84, N; 18.51

Example 15

Preparation of 1- (N-methyl) aminomethyl-5-hydroxymethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1-hydroxymethyl-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane

A solution of 1.54 gr of 1-acetoxymethyl-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane in 50 ml of methanol was dissolved in a solution of 0.65 gr of sodium methoxide in 10 ml of methanol. Add dropwise at room temperature and stir for 30 minutes. The reaction solution was evaporated under reduced pressure, 5% hydrochloric acid was added to the residue, neutralized, and extracted twice with EA (2 × 20 mL). The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to obtain 13.2 gr (yield 98%) of the title compound.

Elemental Analysis for C ₂₂ H ₂₇ NO ₂ :

Calculated Value (%): C; 78.34, H; 8.01, N; 4.15

Found (%): C; 79.07, H; 8.46, N; 4.24

2) Preparation of 1- (N-methyl) aminomethyl-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane

5.30 gr of 1-hydroxymethyl-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane in the same manner as in Example 7) using 70 ml of 40% aqueous methylamine solution The treatment yielded the target compound 4.39 gr (yield 79%).

Elemental Analysis for C ₂₃ H ₃₀ N ₂ O:

Calculated Value (%): C; 78.86, H; 8.57, N; 8.00

Found (%): C; 78.32, H; 8.71, N; 8.37

3) Preparation of 1- (N-methyl) aminomethyl-5-hydroxymethyl-3-azabicyclo [3.1.1] heptane

2.78 gr of 1- (N-methyl) aminomethyl-5-benzyloxymethyl-3- (N-benzyl) azabicyclo [3.1.1] heptane was treated in the same manner as in 2 of Example 13 to give the title compound 2.41 gr (87% yield) was obtained.

Elemental Analysis for C ₉ H ₁₈ N ₂ O:

Calculated Value (%): C; 63.54, H; 10.59, N; 16.47

Found (%): C; 63.14, H; 10.10, N; 16.82

Example 16

Preparation of 1,5-di (N-methyl) aminomethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1- (N-methyl-N-t-butoxycarbonyl) aminomethyl-5-hydroxymethyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

2.78 gr of 1- (N-methyl) aminomethyl-5-hydroxymethyl-3-azabicyclo [3.1.1] heptane and 4.8 gr of di-t-butyldicarbonate were dissolved in 30 ml of methanol and stirred at room temperature for 3 hours. Then, methanol was evaporated under reduced pressure and silica gel column chromatography (n-Hex: EA = 1: 1) gave the desired compound 4.49 gr (yield 94%).

Elemental Analysis for C ₁₉ H ₃₄ N ₂ O ₅ :

Calculated Value (%): C; 61.62, H; 9.19, N; 7.57

Found (%): C; 62.10, H; 9.23, N; 7.71

2) Preparation of 1- (N-methyl-N-t-butoxycarbonyl) aminomethyl-5- (N-methyl) aminomethyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

1.85 gr of 1- (N-methyl-Nt-butoxycarbonyl) aminomethyl-5-hydroxymethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane and 30 ml of 40% methylamine Using the same method as in Example 7 4) to obtain the title compound 2.56 gr (yield 67%).

Elemental Analysis for C ₂₀ H ₃₇ N ₃ O ₄ :

Calculated Value (%): C; 62.66, H; 9.66, N; 10.97

Found (%): C; 63.07, H; 9.14, N; 11.61

3) Preparation of 1,5-di (N-methylaminomethyl) -3-azabicyclo [3.1.1] heptane

2.42 gr of 1- (N-methyl-Nt-butoxycarbonyl) aminomethyl-5- (N-methyl) aminomethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane 4.15 gr (yield 94%) of the target compound were obtained by the same method as 8).

Elemental Analysis for C ₁₀ H ₂₁ N ₃ :

Calculated Value (%): C; 65.57, H; 11.48, N; 22.95

Found (%): C; 65.51, H; 11.36, N; 22.41

Example 17

Preparation of 1- (N-methyl) aminomethyl-5-fluoromethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1- (N-methyl-N-t-butoxycarbonyl) aminomethyl-5-fluoromethyl-3- (N-t-butoxycarbonyl) azabicyclo [3.1.1] heptane

1- (N-methyl-Nt-butoxycarbonyl) aminomethyl-5-hydroxymethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane 3.70gr and N, N-diethyl 1.80 gr of aminosulfetrifluoride was dissolved in 10 ml of methylene chloride, stirred at 0 ° C. for 5 hours, and the reaction solution was evaporated under reduced pressure and neutral alumina tube chromatography (n-Hex: EA = 1: 1) was used to remove 2.75 gr of the target compound Yield 74%).

Elemental Analysis for C ₁₉ H ₃₃ N ₂ O ₄ F:

Calculated Value (%): C; 61.29, H; 8.87, N; 7.53

Found (%): C; 61.84, H; 8.38, N; 7.61

2) Preparation of 1- (N-methyl) aminomethyl-5-fluoromethyl-3-azabicyclo [3.1.1] heptane

2.70 gr of 1- (N-methyl-Nt-butoxycarbonyl) aminomethyl-5-fluoromethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane with 8) of Example 4 The same procedure was followed to obtain 1.14 gr (yield 91%) of the title compound.

Elemental Analysis for C ₉ H ₁₇ N ₂ F:

Calculated Value (%): C; 62.79, H; 9.88, N; 16.28

Found (%): C; 62.10, H; 10.21, N; 16.46

Example 18

Preparation of 1-amino-5-fluoromethyl-3-azabicyclo [3.1.1] heptane

1) Preparation of 1- (N-t-butoxycarbonyl) amino-fluoromethyl-3- (N-t-butoxycarbonyl) zazacyclocyclo [3.1.1] heptane

2.80 gr of 1-amino-5-hydroxymethyl-3-azabicyclo [3.1.1] heptane was dissolved in methanol with 4.36 gr of di-t-butyldicarbonate, stirred at room temperature for 5 hours, and then the solvent was evaporated under reduced pressure. The residue was dissolved in 20 ml of methylene chloride, and 3.60 gr of N, N'-diethylamisulfur trifluoride were added and stirred at 10 ° C for 6 hours. The reaction solution was evaporated under reduced pressure and neutral alumina tube chromatography (n-Hex: EA = 1: 1) gave 4.30 gr (yield 63%) of the title compound.

Elemental Analysis for C ₁₇ H ₂₉ N ₂ O ₄ F:

Calculated Value (%): C; 59.30, H; 8.43, N; 8.14

Found (%): C; 60.14, H; 8.65, N; 8.21

2) Preparation of 1-amino-5-fluoromethyl-3-azabicyclo [3.1.1] heptane

3.42 gr of 1- (Nt-butoxycarbonyl) amino-5-fluoromethyl-3- (Nt-butoxycarbonyl) azabicyclo [3.1.1] heptane was treated in the same manner as 8) 1.34 gr (yield 94%) of target compounds were obtained.

Elemental Analysis for C ₇ H ₁₃ N ₂ F:

Calculated Value (%): C; 58.33, H; 9.03, N; 19.44

Found (%): C; 59.57, H; 9.42, N; 19.56

Claims (13)

3-azabicyclo [3.1.1] heptane derivative of the general formula (I) Wherein n is 1, R ¹ , R ² and R ³ are each a common amino protecting group such as hydrogen, lower alkyl or benzyl, lower alkoxycarbonyl and the like, and R ⁴ is hydrogen or unsubstituted or hydroxy, amino group , Lower alkoxy group, lower alkylamino group or lower alkyl group substituted with halogen. The compound according to claim 1, represented by the following general formula (I a). Wherein R ² is the same as defined in claim 1. The compound according to claim 1, represented by the following general formula (I b). Wherein R ² and R ³ are the same as defined in claim 1. The compound according to claim 1, represented by the following general formula (I c). Wherein R ² and R ⁴ are the same as defined in claim 1. The compound according to claim 1, represented by the following general formula (I d). Wherein R ² is the same as defined in claim 1 and R ⁵ is hydrogen or a methyl group. The compound according to claim 1, represented by the following general formula (I e). Wherein R ^{2 is} the same as defined in claim 1. The compound according to claim 1, represented by the following general formula (I f). Wherein n, R ¹ , R ² and R ³ are the same as defined in claim 1 and R ⁶ is halogen or R ² R ³ N such as fluorine, chlorine or bromine. (1) cyclizing the amine of formula (II) to prepare a compound of formula (III), (2) acylating the compound of formula (III) obtained in step (I) above, and then reducing To prepare a compound of formula (IV), and (3) a method of preparing the following formula (Ia), wherein the compound of formula (IV) obtained in step (2) is debenzylated. . Wherein R ² is the same as defined in claim 1, and R is a methyl group, an ethyl group, a t-butyl group or an isoamyl group. (1) cyclizing the compound of formula (V) to prepare a compound of formula (VI), (2) partially debenzylating the compound of formula (VI) obtained in step (I), After tosylation and reduction, to prepare a compound of the general formula (iii), (3) the compound of the general formula (VII) obtained in the above step (2) mesylated or tosylated, followed by amination and debenzylation A method for producing a compound of formula (I b) below. (1) cyclizing the amine of formula (VII) to prepare a compound of formula (VII), (2) reducing the compound of formula (VII) obtained in step (1) and protecting the amine Thereafter, oxidation was carried out to prepare a compound of formula (VII), and (3) azide or amidated and rearranged the compound of formula (VII) obtained in the above step (2) to formula (XI) To prepare a compound of (4), (4) N-alkylation of the compound of formula (XI) obtained in the step (3), and then deprotection method for producing a compound of formula (I c) . In the above formula, R ² , R ⁴ and R have the same meaning as defined in the above 1 and 2. (1) Debenzylating a compound of formula (XII), protecting the amine, and then oxidizing to produce a compound of formula (XIII), (2) Formula (XIII) obtained in step (1) above. The compound of Formula (VII) was prepared by azides or amidated and rearranged to prepare a compound of the following Formula (VII), and (3) N-alkylated the compound of Formula (VII) obtained in step (2) above, A process for preparing a compound of formula (I d) below, characterized by deprotection. Wherein R ² and R have the same meaning as defined in the above 1 and 2, and R ⁵ is hydrogen or methyl group. (1) Deprotecting the acetoxy group of the compound of general formula (XII) to produce the compound of formula (VV), and (2) amination of the compound of general formula (XV) to prepare the compound of formula (XIV). And (3) debenzylating the compound of the general formula (XIV). Wherein R ² is the same as defined in claim 1. A process for producing a compound of formula (I f), wherein the compound of formula (VIII) is halogenated or aminated. Wherein R ¹ , R ² and R ³ are the same as defined in 1 above, and R ⁶ means halogen or R ² R ³ N— such as a fluorine atom, a chlorine atom or a bromine atom.