JPS5946515B2 - New tricyclic cage-shaped amine compound - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to Ξ cyclic cage amine compounds.

In other words, the present invention relates to a novel Ξ-cyclic cage-shaped amine compound represented by the general formula [1] and useful as a pharmaceutical, and an acid salt thereof. Tonhe~−” [In the formula, −
The group represented by A and -NH2 represents an amino group, aminomethyl group or α-aminoethyl group bonded to the 2- or 3-position, and A2 and As represent a methylene or ethylene chain.

(However, this excludes those in which Al is a single bond or a methylene chain when bonded to the 3-position and A2 and As are methylene or ethylene chains at the same time)] The compounds of the present invention represented by the general formula [I] can be used in various Viruses such as influenza virus, herpessus impletus virus (He
It has a remarkable suppressive effect against viruses such as Rpessimplexvirus.

By the way, as a cage-like amine compound having antiviral activity, amantadine (Amanta-dine) is already known.
■MerkIndex9thP, 367-368) is well known.

Based on its remarkable anti-influenza virus activity, amantadine is already in clinical use as an anti-influenza agent in the United States.

On the other hand, amantadine has also been developed for use as an anti-Parkinsonian drug due to its strong central effects such as anti-catalepsy action, and is now being put into clinical practice in Japan and other countries. As described above, although amantadine has strong anti-influenza activity and is useful as an anti-influenza agent, its use as an anti-influenza agent is severely limited due to its strong central action. Under these circumstances, the present inventors have been intensively investigating the search for cage-shaped amine compounds that have antiviral effects but do not have central effects, or have substantially weaker central effects than antiviral effects. The inventors discovered that the compound of the present invention is a compound that meets this purpose, and completed the present invention. The novel tricyclic cage-shaped amine compound represented by the general formula of the present invention has a characteristic skeleton (oxa-type cage skeleton) with an ether bond in the ring, and is a novel compound synthesized for the first time by the present inventors. It is a group.

In the novel tricyclic cage-shaped amine compound represented by the general formula [1] of the present invention, A1 represents a single bond, a methylene chain or an ethylidene (methylmethylene) chain, and therefore a group represented by -A1-NH2 represents an amino group, an aminomethyl group or an α-aminoethyl group bonded to the 2nd or 3rd position of the Osaki cage-like skeleton. The method for synthesizing the compound of the present invention is achieved through various synthetic routes and synthetic reactions as shown in the examples below, but is basically based on the following principles.

That is, a diene compound, cyclopentadiene or cyclohexadiene, is used as a starting material, and this is subjected to a Diels-Alda reaction with a dienophile to form bicyclo[
2,2,1] Heptene derivatives to bicyclo[2,2,2
] Obtain an octene derivative. The dienophilyl used here has a substituent that can later be converted into an amino group or an aminoalkyl group.

The bicycloheptene or bicyclooctene derivative obtained here is crosslinked using the endo coordination substituent to form a cage-shaped tricyclic compound. On the other hand, bicyclo[2,2,1]heptene derivatives or bicyclo[2,2,1]heptene derivatives, which can be said to be intermediates in the first step leading to O compounds of the present invention, which are achieved by converting the remaining substituents into amino groups or aminoalkyl groups. Bicyclo [
2,2,2] The synthesis of octene derivatives is performed using a diene compound (1
), that is, it can be synthesized by a Diels-Alda reaction using cyclopentadiene or cyclohexadiene as raw materials.

That is, additives (8 (3) (4), (5)) containing already well-known compounds obtained as dienophiles such as maleic anhydride, fumaric acid ester, itaconic anhydride, glutaconic acid ester, methylene malonic acid ester, etc. ,(6)
etc. can also be used in the synthesis of the compounds of the present invention. [In the formula, R represents a hydrogen atom or a lower alkyl group, and A has the same meaning as above. ]The second step to obtain the compound of the present invention is
By carrying out a crosslinking reaction using the endo coordination substituent of the previously obtained bicyclo[2,2,1]heptene derivative or bicyclo[2,2,2]octene derivative to form a tricyclic cage-like compound. be.

Note that the remaining substituents are for ultimately forming the amino group or aminoalkyl group of the compound of the present invention, and the conversion reaction can be carried out as appropriate prior to the crosslinking reaction.

Several reaction modes are applicable for crosslinking, and preferred examples are shown below.

of Bu where A2 and A3 have the same meaning as before.

A} represents a single bond, in this case Y is a carboxyl group,
represents a substituent convertible into an aminoalkyl group such as an alkoxycarbonyl group, formyl group, cyano group, carbamoyl group or acyl group, or ' or A1 represents a single bond, a methylene chain or a methylmethylene chain, in which case Y
represents a substituent that can be converted into an amino group such as a hydrosyl group, a halogen group, a nitro group, an acylamino group, a phthalimide group, an alkoxycarbonylamino group or a benzylamino group.

A'! represents a single bond or a methylene chain. That is, the adduct product previously obtained by the Diels-Alda reaction is chemically converted as required to lead to the carboxylic acid compound (9) or alcohol derivative (self) suitable for the crosslinking reaction.

Carboxylic acid derivative (9): An iodolactone (self) is obtained by an iodolactonization reaction, and the iodo group is reductively eliminated to obtain a lactone (self).

The lactone group is reduced to form a diol (auto), and the diol group is subjected to dehydration condensation to obtain the desired oxa-type cage-shaped tricyclic compound A4). Also, alcohol derivative a
ω is obtained by a haloetherification reaction to obtain a bromine ether, and the bromine group is reductively eliminated to obtain the desired oxa-type cage-like ternary compound A4), or the alcohol derivative A9) is obtained by converting it into an oxymer compound. The desired oxa-type cage-shaped tricyclic compound (14') can be directly obtained by a reaction.

The final step to obtain the compound of the present invention is to convert the previously obtained compound (self) or (14 remaining substituents into the desired amino group or aminoalkyl group).

Compound A4) or (14 Y is a carboxyl group, an alkoxycarbonyl group, a formyl group, a cyano group,
Examples include a carbamoyl group, an acyl group, a hydroxy group, a halogen group, etc., and these can be converted into the desired amino group or aminoalkyl group by a normal chemical reaction or a combination thereof.

Further, when Y is a protected amino group such as an acylamino group, a phthalimide group, an alkoxycarbonylamino group, or a benzylamino group, the purpose can be achieved by removing these protecting groups.

Some examples of synthesis of the compounds of the present invention will be described in more detail below.

(1) Example of a compound in which the amino group is connected to the 2-position by a single bond in the general formula [1] [wherein A2 and A'3 have the same meanings as above] Compound A6) is converted to 12- The iodolactone compound (self) was obtained by treating it in a NaHCO3 aqueous solution using KI, and the compound (self) was converted into an acid azide by a mixed acid anhydride method, and then converted into an isocyanate by a Curtius rearrangement reaction, and then converted into an isocyanate using ethanol. Compound A8) is obtained.

React the compound (self) with tributyltin hydride,
After the lactone form (self) is obtained, it is reduced with calcium boron hydride in ethanol to obtain the diol form (yield).

Compound 20) is etherified using tosyltalolide in pyridine to obtain Compound (Compound). The desired amine compound 1 can be obtained by subjecting Compound (Compound) to a hydrolysis reaction in an aqueous caustic potassium solution. When A3 of the amine compound (22) is an ethylene chain, it can also be obtained as follows.

A Diels-Alda reaction using a dienophile reactor yields (2) and (24). The chloro group of (2) is converted to a hydroxyl group to obtain (24). A crosslinked ether (2) is obtained by reacting with mercuric acetate (mercuric acetate) and sodium borohydride. Compound (1) is converted into a carboxylic acid (5), and this is subjected to a Curtius rearrangement reaction to form a compound (
This can be further hydrolyzed to obtain the target compound.

(Ii) Example of a compound in which A is a methylene chain bonded to the 2-position in the general formula [1] A diester is reduced with lithium aluminum hydride in tetrahydrofuran,
Diol Co., Ltd. h is obtained.

Compound (C) is reacted with N-bromosuccinimide in a mixed solvent of chloroform and tetrahydrofuran to form a bromoether (C), which is reduced with tributyltin hydride to obtain Compound (C). Compound (2) can also be obtained by reacting compound (2) with mercuric acetate (or mercuric trichloroacetate) and sodium borohydride. The compound (sol) is tosylated with tosyl chloride in pyridine, and then treated with sodium bromide to obtain the bromo compound (sol). This is phthalimidated to obtain compound (2). The target compound (II) can be obtained by subjecting the compound (I) to a deptalol group reaction. The compound (III) can also be easily obtained by reducing the cyano compound (I) or the carbamoyl compound (I) with lithium aluminum hydride as described below.

[In the formula, A2, A3 and R have the same meanings as above.
] (Example of a compound in which A1 is a methylmethylene chain in the general formula [1] (a) A halogen group can be mentioned as a substituent that is bonded to an alkylene chain and can be converted into an amino group.

Further, when the substituent is a protected amino group such as an acylamino, benzylamino, phthalimide, or alkoxycarbonylamino group, the desired amino group can be formed by removing the protecting group after ring formation. (b) A,
The formation of the methylmethylene chain moiety represented by is carried out after the formation of an adduct by the Diels-Alda reaction, or during the ether crosslinking reaction process, or after the completion of the ether crosslinking reaction (after the formation of the oxa-type tricyclic cage skeleton). You can also do it. Examples of intermediates suitable for this purpose include the following compounds (C), (C), (3), and the like.

[In the formula, A2, A3 and R have the same meanings as above.
] The compound group obtained by the present invention is named using the following names.

That is, the prentane derivative has the following structure.
Homopretentane derivatives have the following structures, isotwistane derivatives have the following structures, and homoisotwistane derivatives have the following structures.

For other skeletal systems, IUPAC nomenclature will be used.

According to the present invention, for example, the following compounds can be obtained.

5-oxa-2-aminomethyl-brendan 5-oxa-2-aminoisotwistane 5-oxa-2-aminomethyl-isotwistane 6-oxa-2-amino Homoblendan 6-oxa-2-aminomethyl-Homoblendan 5-oxa-2-(α-aminoethyl)-Prentane 5-oxa-2-(α-aminoethyl)-isotwistane 5-oxa-3-(α- aminoethyl)-prentane 5-oxa-3-(α-aminoethyl)-isotwistane 6-oxa-3-(α-aminoethyl)-homoprenetane 6-oxa-3-(α-aminoethyl)-homisotwistane The above general formula [1] obtained by the present invention
Since the compounds are amine derivatives, they can optionally contain physiologically harmless inorganic and organic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, Acid addition salts such as fumaric acid and succinic acid can be formed.

EXAMPLES The present invention will be specifically illustrated below with reference to Examples and Reference Examples, but the present invention is not limited thereto.

Example 1 5-norbornene-2,3-dicarboxylic anhydride 2169
and water 7209, and concentrated H2SO46609 was gradually added dropwise at room temperature.

After adding 2 liters of boiling water and filtering, the mother liquor was cooled to obtain white crystals of 5-oxa-4-oxo-2-carboxy blendan 2009. Melting point 192-193℃ IRvN0
j01; 1780, 1690, 1260, max anhydrous 2
,3-dicarboxylic acid-bicyclo[2,2,2]oct-
Add 5-ene 259 to 200 ml of 5% sodium hydrogen carbonate, heat under reflux for 2 hours to hydrolyze the acid anhydride, cool, and perform iodolactonization with 12-KI solution according to a conventional method. After stirring at room temperature for 3 hours. d10% Hypo aqueous solution was added to consume the excess 2, concentrated hydrochloric acid was added to make it acidic, the precipitated crystals were filtered and recrystallized from chloroform to obtain the desired 10-iodo-5-oxa-4-oxo-2- Carboxyisotwistane 359 was obtained.

Melting point 191-193°C IRvN0j01; 1790,1
780, 1730, 1710max Example 2 Add 10 fl of 5-oxa-4-oxo-2-carboxy blendan to 140 ml of dichloromethane, and add DMF2
Add 83 ml of thionyl chloride dropwise and heat under reflux for 3 hours.

After distilling off the solvent, add an appropriate amount of benzene and re-distilling.
33.939 NaN was added to 40 m' of dry acetone, and 50 m' of the above-mentioned acid chloride solution in dry acetone was added at room temperature. After stirring for 2 hours, the mixture was extracted with water-chloroform. M
After drying with gSO4, the mixture was concentrated, 100 ml of ethanol was added, and the mixture was heated under reflux for 2 hours. After distilling off the ethanol, 6.99 g of white crystals of 5-oxa-4-oxo-2-ethoxycarbonylamino blendan were obtained. Melting point 119~
120℃ (benzene reconsolidation) IRvN0j01; 3250
, 3140, 1780, 1720max, the following compounds were obtained in the same manner.

10-iodo-5-oxa-4-oxo-2-carboxyisotwistane 39 as a white crystal 10-iodo-
5-Oxa-4-oxo-2-ethoxycarbonylaminoisotwistane 29 was obtained.

Melting point 158-159℃ (acetic acid ethyl hexane reconsolidation) ■Rv
NUj0! ;3300,1800,1690,1550
Max Example 3 3.89 10-iodo-5-oxa-4-oxo-2-ethoxycarbonylaminoisotwistane was added to 60 ml of tetrahydrofuran, and further 6.09 ml of tributyltin hydride and 100711 azobisisobutyronitrile were added.
Add l9 and stir at room temperature for 4 hours.

After extraction with a water-n-hexane system and re-extracting the n-hexane layer with water, the aqueous layers are combined and extracted with chloroform. After drying with magnesium sulfate, chloroform is distilled off. 1.39% of 5-oxa-4-oxo-2-ethoxycarbonylaminoisotwistane was obtained.

Melting point 157-159°C (isopropyl ether reconsolidation) I
RvN0j01; 3300, 1780, 1700, 15
The following compounds were obtained in the same manner as 40max.

14.3 g of oily 5-oxa-2-hydroxymethyl-brendan was obtained from 25.49 g of 9-bromo-5-oxa-2-hydroxymethyl-brendan.

film IRν; 3400, 1440, 1360maX1
From 0-bromo-5-oxa-2-hydroxymethyl-isotwistane 109, oily 5-oxa-2-hydroxymethyl-isotwistane 5.29 was obtained.

■RVf11rT1; 3500, 1100, 1080m
ax Example 4 Sodium borohydride 1.169 to diglyme 60m
Lithium chloride (1.39 g) was added to the solution, and the mixture was stirred at room temperature for 1 hour.

Dissolve 6.99 ml of 5-oxa-4-oxo-2-ethoxycarbonylamino blendan in 12 ml of diglyme and add.

Stir for 3 hours while heating to 90-100°C, cool, and add N
Excess hydride was decomposed by adding H4Cl, extracted with chloroform, dried with magnesium sulfate, and the solvent was distilled off and concentrated.
．． 39 5-endohydroxy-3-endohydroxymethyl 2-ethoxycarbonylamino mononorbornane was obtained.

IRvN0j01;3430,3350,3250,1
The following compounds were obtained in the same manner as 700 and 1520max.

5-oxa-4-oxo-2-ethoxycarbonylamino-isotwistane 790~5-endo-hydroxy-3-endo-hydroxymethyl-2-ethoxycarbonylaminobicyclo[2,2,2]-octane 700η I got it.

IRvNUjOl;3600,3100,1720,m
ax1700,1520 Example 5 5.79 of 5-endo-hydroxy-3-endo-hydroxymethyl-2-ethoxycarbonylaminonorbornane was added to 20me of pyridine, 5.79 of p-toluenesulfonyl chloride was added under water cooling, and then the mixture was heated to room temperature. Encourage a reaction.

After stirring for 12 hours, the mixture was made acidic by adding 10% aqueous hydrochloric acid and extracted with chloroform.

After washing with saturated sodium carbonate water and saturated saline, dry over magnesium sulfate and concentrate. After purification by column chromatography, oily 5-oxa-
3.59% of 2-ethoxycarbonylamino blendan was obtained. FiImIRν; 3300, 1700,
The following compounds were obtained in the same manner as 1540 and 1200max.

5-Endo-hydroxy-3-endo-hydroxymethyl-2-ethoxycarbonylaminobicyclo[2
,2,2]Octane 700 Whiter solid 5-oxa-2-ethoxycarbonylamino-isotwistane 20
Obtained 0m9.

Melting point 83-84℃ IRVflnnl; 3320,172
0,1540,1260max Example 6 5-oxa-2-ethoxycarbonylamino blendan 49 was added to 100 ml of a 15% aqueous potassium solution and heated under reflux for 2 hours.

After extraction with chloroform, the extract was washed with saturated brine, dried over magnesium sulfate, and concentrated to obtain 2.39 g of 5-oxa-2-aminobrendan as an oil. Film IRν; 3300, 3250, 1380, 110
0max This compound crystallized when left at room temperature for one week.

The following compound was obtained in the same manner with a melting point of 68-69°C.

From 1.39 of 5-oxa-2-ethoxycarbonylamino-isotwistane, 0.549 of oily 5-oxa-2-amino-isotwistane was obtained.

FilmIRν: 3350, 3280, 2940
, max1590,1090 Example 7 5-norbornene-2,3-dicarboxylic anhydride 16.4
9 was added to 100 ml of methanol, 5.49 ml of sodium methoxide was added, and the mixture was stirred for 12 hours.

Thereafter, the mixture was made acidic by adding 10% hydrochloric acid, extracted with acetic acid, washed with saturated saline, and dried with magnesium sulfate. Concentration gave 3-carboxy-2-methoxycarbonyl-5-norbornene 199 as white crystals. Melting point 101~
102℃ (benzene-ligroin reconsolidation) KBr IRν; 2950, 1740, 1720, 120
0max This compound crystallized when left at room temperature for one week.

The following compound was obtained in the same manner with a melting point of 83-84°C.

3-carboxy-2-methoxycarbonyl bicyclo[2,2,2]oct-5 from 2,3-dicarboxylic anhydride-bicyclo[2,2,2]oct-5-ene 18,69
-yene 14.79 was obtained.

Melting point 95-99°C (isopropyl ether reconsolidation) IRv
NUjOl;3300,1730,1710,max1
420,1040 Example 8 3-Carboxy-2-methoxycarbonyl-5-norbornene 11,69 was dissolved in 260 ml of acetone, -2
After adding triethylamine Z839 at 0°C, 7.79 g of ethyl chlorocarbonate was added, and the mixture was stirred at the same temperature for 20 minutes.

The reaction solution was cooled to -30°C and sodium azide 5.69%
A solution prepared by dissolving . The desired product was extracted with benzene, and after drying, the solvent was distilled off. The resulting oil was heated under reflux with ethanol to obtain the desired oily 3-ethoxycarbonylamino-2-methoxycarbonyl-5-norbornene 139. Film.
Rν; 3400, 3000, 1720, 1520
The following compounds were obtained in the same manner as max.

3-carboxy-2-carboxymethyl-bicyclo [
3-ethoxycarbonylamino-2-methoxycarbonylbicyclo[2,2,2]oct-5-ene 2,29 was obtained from 2,2,2]oct-5-ene 2.19.

Melting point 63-64℃ ■RvNUj01; 3370,173
0,1710,1520max Example 9 Calcium chloride 3.29, Sodium borohydride 1.
49 was added to 30me of ethanol and stirred at room temperature to give 3-ethoxycarbonylamino-2-methoxycarbonyl-5-
A solution prepared by adding 1.89 g of norbornene to 10 ml of ethanol is added dropwise.

After stirring at room temperature for 4 hours, it is extracted with chloroform-ammonium chloride. After washing with saturated saline, drying with MgSO4. 1.59 g of oily 3-ethoxycarbonylamino-2-hydroxymethyl-5-norbornene was obtained. fi1
mIRν: 3500, 2870, 1720, 15
The following compounds were obtained in the same manner as 20max.

3-Ethoxycarbonylamino-2-methoxycarbonylbicyclo[2,2,2]oct-5-ene 2.09
1.99 of oily 3-ethoxycarbonylamino-2-hydroxymethyl-bicyclo[2,2,2]oct-5-ene was obtained.

filmIRν; 3500, 2950, 1710
, 1520max Example 10 Mix 2.59 mercuric acetate, THF and 10 ml of water,
Add 1,59 lbs of 3-ethoxycarbonylamino-2-hydroxymethyl-5-norbornene at room temperature.

After stirring for 3 hours, 1 mj of 3N-NaOH water was added, followed by 200 w of sodium boron hydride, and the mixture was stirred at room temperature for 2 hours. The extract was extracted with chloroform, washed with saturated saline, and concentrated to obtain 1.29 g of 5-oxa-2-ethoxycarbonylamino blendan. The physical properties were the same as in Example 5, and the following compounds were obtained.

3-Ethoxycarbonylamino-2-hydroxymethyl-bicyclo[2,2,2]-oct-5-ene 1.8
From No. 9, 14 g of white solid 5-oxa-2-ethoxycarbonylaminoisotwistane was obtained.

Melting point: 83-84°C Physical properties are consistent with Example 5 2,3-dihydroxymethyl-5-norbornene 3.
From No. 09, 2.59 of oily 5-oxa-2-hydroxymethyl-blendazole was obtained.

The physical property values matched those of Example 3.

2,3-dihydroxymethyl-bicyclo[2,2,2
] Oily 5-oxa-2-hydroxymethyl-isotwistane 69 was obtained from oct-5-ene 69.

Example 11 409 of anhydrous 5-norbornene-2,3-dicarboxylic acid and 109 of lithium aluminum hydride were heated under reflux in tetrahydrofuran to obtain 159 of 2,3-dihydroxymethyl-5-norbornene as a white solid.

Melting point 82-3℃ IRvNUj01: 3300-3200
, 1220, max, the following compounds were obtained.

2,3-dicarboxylic anhydride monobicyclo[2,2,2]oct-5-ene 109 White solid 2,3-dihydroxymethyl-bicyclo[2,2,2]oct-5-
I got en69.

Melting point 94.5-95℃ (benzene-hexane) IRνN
0j01; 3200-3300, 1210, max10
30,1020 Example 12 2,3-dihydrothousymethyl-5-norbornene1.
549 with 10 ml of tetrahydrofuran and 1 ml of chloroform
Dissolve in 0 ml of N-bromosuccinimide (NB) under ice-cooling.
S) was added and stirred at room temperature for 1 hour.

After adding a small amount of Hypo aqueous solution and consuming excess NBS,
The target product was extracted with chloroform. oily 9-fromo-
5-oxa-2-hydroxymethyl-brendan 2,
I got 19. film. IRν: 3400, 1460, 1220, 11
The following compounds were obtained in the same manner as 00max.

2,3-dihydroxymethyl-bicyclo[2,2,2
] Oct-5-ene 69 to oily 10-bromo-5-
Oxa-2-hydroxymethylisotwistane 59 was obtained.

Film Rν; 3450, 1460, 1210, 1100
max Example 13 5-oxa-2-hydroxymethyl-brendan 14
, 39 was added to 100 ml of pyridine, and 17.1 g of P-toluenesulfonyl chloride was added while stirring under ice cooling.

After stirring for 12 hours, the mixture was acidified with hydrochloric acid and extracted with chloroform.

The white crystal 5-oxa-2-p-tolylsulfonyloxymethyl-brendan 21.69 obtained here and LiB
Add 22 fl of r to 200 ml of methyl ethyl ketone and heat under reflux for 3 hours. After evaporation of the solvent, extraction with water-chloroform, and concentration, 15.79% of oily 5-oxa-2-prommethyl-brendan was obtained. Film. Rν; 2950, 1220, 1050, 800
The following compounds were obtained in the same manner as max.

Oily 5-oxa-2-prommethyl-isotwistane 69 was obtained from 5-oxa-2-hydroxymethyl-isotwistane 159.

Film. IRν; 2950, 1230, 1040max
Example 14 5-oxa-2-prommethyl-Brendan 109 and phthalimide potash 9.19 are dimethylformamide 150
ml and heated at 150°C for 5 hours.

After cooling, the mixture is extracted with 5% Na2cO3 water and benzene and concentrated. 4.39 of a white solid 5-oxa-2-phthalimidomethyl-brendan was obtained. Melting point 123-124℃ (
Isoprobyl alcohol recondensation) IRvNOjOl: 1
780,1700~1720max251470,14
Same as 40? The compound below was obtained.

From 5-oxa-2-prommethyl-isotwistane 69, 4.79 of a white solid 5-oxa-2-phthalimidomethyl-isotwistane was obtained.

IRVpi! 1; 3200,2800-3025,178
0,1700-1770 Example 15 5-oxa-2-phthalimidomethyl-brendan 3,
859 was added to 40 ml of ethanol, and after dissolving, 1.2 f1 of hydrazine was added dropwise, and heating was continued under reflux for 1 hour.

After cooling, add 20ml of 10% hydrochloric acid, heat to 50-60°C, and stir for 20 minutes. Next, 10% aqueous soda was added to neutralize the mixture, followed by extraction with chloroform. 1.6 g of the desired oily 5-oxa-2-aminomethylprentane was obtained. FiI
m. I Rν: 3300, 3250, 2950, 110
The following compounds were obtained in the same manner as above.

0.7' of oily 5-oxa-2-aminomethyl-isotwistane was obtained from 4.3 g of 5-oxa-2-phthalimidomethyl-isotwistane.

Film IRν ;3350,3280,2950;146
0max Example 16 3-endo-(β-chloroethyl)-2-exo-methoxycarbonyl-5-norbornene 19 and potassium acetate 59
After dissolving 1 ml of acetic acid in 5 ml of dimethylformamide and heating at 120°C for 3 hours, the target product was extracted with benzene to obtain an oily 3-endo-(β-acetoxyethyl)-2-
Exo-methoxycarbonyl-5-norbornene 19 was obtained.

FiImRν; 1740, 1430, 1360m
ax Example 17 3-endo(β-acetoxyethino(ha)-2-exo-methoxycarbonyl-5-norbornene 19 was reacted with COnc, H2sO4 in methanol under stirring at room temperature to obtain the desired 3-endo-(β- hydroxyethyl)-2-exo-methoxycarbonyl-5-norbornene 850η
was obtained as an oil.

FilmIRν: 3400, 1730, 1430
, 1240n1ax Example 18 Mercury oxide 2.69, trichloroacetic acid 4.029, water 50
A solution of 1.96 g of 3-endo-(β-hydroxyethyl)-2-exo-methoxycarbonyl-5-norbornene in tetrahydrofuran was added dropwise.

After stirring for 24 hours, 80 W of 3N NaOH water and 1.09 W of LI sodium borohydride were added, followed by stirring at room temperature for 3 hours.

The mixture was acidified with hydrochloric acid and extracted. The obtained 6-oxa2-carboxyhomobrendan 3.09 and triethylamine 2
, 239 was added to 50 ml of acetone, and 2.219 ml of ethyl chlorocarbonate was added dropwise at -20°C. After stirring for 20 minutes,
NaN3l. at -30°C. Add 49 and further heat at -20℃ for 1
Stir for an hour.

After completion, extract with benzene and concentrate.

100 mj of ethanol was added and heated under reflux for 5 hours.
The product was purified by column chromatography, and 0.89 g of the desired oily 6-oxa2-ethoxycanolevoninoleamino homoblendan was obtained from the chloroform eluate. Fi! MIRν: 3340, 2960, 1720, 154
0max Example 19 0.81 of 6-oxa-2-ethoxycarbonylamino-homobrendan was added to 30 ml of 15% potassium and heated under reflux for 7 hours.

After the reaction, the mixture was extracted with chloroform to obtain 100 g of oily 6-oxa-2-aminohomobrendan. Film IRν: 3350, 3280, 1590, 139
0max Example 20 119 methyl α-cyanoacrylate and 8.09 ml of 1,3-cyclohexadiene were added to 100 mj of benzene, heated under reflux for 3 hours, and after cooling, the solvent was distilled off to obtain an oily exo-12-cyano-endo- 2-Methoxycarbonylrubicyclo[2,2,2]oct-5-ene 189 was obtained.

Film IRν: 2950, 2875, 2250, 175
0, max1440,1270,1260,1220,
Example 21 The following compound was obtained in the same manner as in Example 9.

Exo-2-cyano-endo-2-methoxycarbonylbicyclo[2,2,2]oct-5-ene to oily exo-2-cyano-endo-2-hydroxymethyl-bicyclo[2,2,2]octo 15-ene was obtained. Fi
lm Rν; 3400, 2240, 1470, max1
460,1380 Example 22 The following compound was obtained in the same manner as in Example 10.

Exo-2-cyano-endo-2-hydroxymethyl-bicyclo[2,2,2]oct-5-ene to solid 5
-oxa-3-cyanoisotwistane was obtained. melting point
105℃ IRvNUjOl: 2250, 1480, 1440, m
ax1340, 1080, 1040 Example 23 2.29 of 5-oxa-3-cyanoisotwistane is added to ether 107!11, and an ether solution of methyllithium (20 mm0I) is added dropwise at room temperature in a N gas flow.

After stirring at room temperature for 6 hours, 10% aqueous hydrochloric acid was added, and the reaction solution was further extracted with benzene. Drying and concentration gave 1.59 g of 5-oxa-3-acetylisotwistane as an oil. Film IRν (礪-1): 2950, 1700, 1440
, max 1360, 1280 Further, this oxime derivative was obtained by a conventional method.

Melting point 87-90℃ IRvNUjOl: 3300,128
0,1000,890max Example 24 5-oxa-3-acetylisotwistane oxime (
900η) was added to 20d of tetrahydrofuran, 700ml of lithium aluminum hydride was added, and the mixture was heated under reflux for 8.
I spent time.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, the group represented by -A_1-NH_2 is an amino group, aminomethyl group, or α-
An aminoethyl group, A_2 and A_3 represent methylene or ethylene chains. (However, when bonded to the 3-position, A_1 is a single bond or a methylene chain, and at the same time, A_2 and A_3 are methylene or ethylene chains are excluded)] and their acid salt.