CA2049047A1 - Process for producing carboxetanocin g or a intermediate therefor - Google Patents
Process for producing carboxetanocin g or a intermediate thereforInfo
- Publication number
- CA2049047A1 CA2049047A1 CA002049047A CA2049047A CA2049047A1 CA 2049047 A1 CA2049047 A1 CA 2049047A1 CA 002049047 A CA002049047 A CA 002049047A CA 2049047 A CA2049047 A CA 2049047A CA 2049047 A1 CA2049047 A1 CA 2049047A1
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- Prior art keywords
- formula
- compound
- solvent
- dissolved
- distilled
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C219/24—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/04—Systems containing only non-condensed rings with a four-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT
This invention relates to a process for producing carboxethanocin G represented by formula (II):
(II) or carboxethanocin A represented by formula 9:
9 both expected to be useful as antiviral agent, and to cyclobutane derivatives represented by formula 5:
This invention relates to a process for producing carboxethanocin G represented by formula (II):
(II) or carboxethanocin A represented by formula 9:
9 both expected to be useful as antiviral agent, and to cyclobutane derivatives represented by formula 5:
Description
7s5664 - 1- ,~ ' PROCESS FOR PRODUCING CARBOXETANOCIN G OR A
AND INTERMEDIATE THEREFOR
'' .:' ~' 1 [TECHNICAL FIELD] -This invention relates to a process for producing carboxetanocin G or carboxetanocin A having an antiviral activity and expected to be useful as an antiviral agent, and to an intermediate for them.
.
[P~IOR ART]
: Ever since the isolation of the carbocyclic analogues of naturally occurring adenosine such as aristelomycin ~T. Kusaka et al., J. Antibiot., 21, 255 (1968)) and nepranocin (S. Yaginuma et al., ibid., 34, 359 (1981)), the syntheses of carbocyclic analogues of purine and pyrimidine nucleoside have been watched with interest.
.
CH ~ CH
HO ~ ~ HO ~
OH OH OH OH
Aristelomycin Nepranocin Oxetanocin A, recently reported, is a novel oxetanosyl-N-glycoside isolated from culture product of Bacillus , .. . .. . . . . .
( l megaterium, and it has antiviral, antitumorigenic and antibacterial activaties (N. Shimada et al., J. Antibiot., .
39, 1623 (1986)).
NH2 ' ' / CH
~~ " - ', ''` ' ~/
`' CH2 \
, ` Oxetanocin A
In view of the above, the present inventors :~
~5 attempted to synthesize other carbocyclic analogues of oxetanocin A. : -, [DISCLOSURE OF THE INVENTION]
: :
:In the first aspact, this invention relates to a process for synthesizing carboxetanocin G represented by formula (II):
' . ~ . . ~ ~ ................... . ..
- .
O
`' ' ~t/ :., ~ HOH C ~ ~
.1~ ~',',';.' 1 characterized by treating a compound represented by ` ~:
formula (I):
~ .
i3,~ , ?~.
Cl N
H2N ,,.,~. , 1 ~ COOH C I I ~
", ' H2C ;`
: with an alkali hydroxide, followed by treating it with an acid.
: 5 In~the second aspect, thls invent1on relates to `~
a process or producing carboxetanocin A represented by '~
formula 9~
.',','....
'' : '',,, NH
. .
HOCH N ~ N 9 ;',, ~ "~ ' .~ y ., I
:1 ~ H2H
.
:i :
~ .
1 characterized by treating a compound represented by formula 8~
' -NH2 :;
COOCH~ N ~N j 8 ~ ` .
~ ~ ~ A
~ CH20CO ~) ' `~ with an alkali hydro~ide.
, In the third aspect, this invention relates to cyclobutane derivatives represented by formula 5:
: P-OCH2 ': y CH O P ~ :
.
~ 5 ~
1 wherein P is a protecting group for hydroxyl group, which are useful as an intermediate for these carboxetanocins.
In the first place, the first aspect of this invention will be explained.
In the invention of the first aspect, as the alkali hydroxide, alkali metal hydroxides such as sodium ;~ hydroxide, lithium hydroxide, potassium hydroxide and the like can be referred to, for example. Among them, sodium hydroxide is general and preferable. As its amount, an i 10 amount of 1.5 ml or above, for example, as lN solution per 0.44 mmole o the compound of formula (I) is sufficient.
Usually it is used in an amount of about 2 ml. Though the reaction temperature is not limited, room temperature is sufficient.
A solvent for the compound of formula (I) is not limited, so far as it dissolves the compound of formula .
(X) and excercises no adverse influence on the reaction. ,~, -Dio~ane and the like are referred to, for example.
As the acid, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and the like can be referred to, among which hydrochloric acid is general and~
preferable. Although its amount varies depending on the . .
amount of the alkali hydroxide used in the preceding step, it is usually 2 ml or above as lN hydrochloric acid per 0.44 mmole of the compound of formula (I), and an amount of about 3 ml is practically advisable.
The reaction with acid can be carried out by adding an acid to the reaction liquid obtained by --' ,`'.
. .
~o ~ L;~-~,3 ~ ~ i ; 1 the above-mentioned reaction with sodium hydroxide, pre~erably concentrating it, and then making the reaction progress preferably in the neighborhood of boiling point of the solvent.
: 5 After completion of the reaction, purification -~
treatment such as chromatographic treatment, recrystal-lization or the like is carried out, whereby ; carboxethanocin G represented by formula (II) is obtained.
The compound of formula (I) used as starting material can be obtained according to the following reaction scheme from a compound of formula 5a mentioned below.
:
, .
'`
, .
:.":. . ~,:
- 7 ~ t~
" U ',",',:'':.
`J ~
~ ~v 3 $ g o , .~,` , ~ ~
.,,. ~V . -- ~.
o\~
Z 4 o ~z ~ ~ o ~ ~ b E
` ~ 8 ~ .
~N~3 b o ~ 0~o ~ ~
N ~ ~z ~ N ~
~ ' Z Z~ o ~ b EQ'~
; O m ~ ' '', o~ ~:
r~
, . , . , ~ , . . .. .. ; . . ~ : ' - .. . .
J
1 Next the second aspect of this invention will be explained.
As the alkali hydroxide used in the second aspect of this invention, the same ones as mentioned in ; 5 the first aspect of this invention can be referred to, among which sodium hydro~ide is general and preferable.
As its amount, an amount of 0.7 ml or above as lN aqueous solution per 0.23 mmole of the compound of formula 8 is sufficient. Usually, it is used in an amount of about 1 ml. The reaction temperature is not limited, and room temperature is sufficient.
As a sol~ent for the reaction, any solvent may be used without limitation so far as it dissolves the compound of formula 8 and exercises no adverse influence on the reaction. As examples of the solvent, alcohols such as methanol, ethanol and the like can be referred to.
After completion of the reaction, purification treatment such as column treatment, recrystallization or the like is carried out, whereby carboxethanocin A
represented by formula 9 is obtained.
~ The compound of formula 8 can be obtained i according to the following reaction scheme by using a compound of formula 5a mentioned below as a starting material.
g ~ 7 ,:, . ~ -. .
~ .`
. ~
o~o o ~
~æ Q
æ~z v u~
o o c o o .. o\O
, ~ ~o r, .~.-~ l o\o æ ~ ~ 1 ,` ,, ~ ~r -~ ~ ~ .
~ Q ~z Q
o o z\ o ~ ot~S -~ ~ < ~
cN~
O ~ O ' ~' O O
- 10- 2~V~
1 Next, the third aspect of this invention will be explained.
In the third aspect of this invention, as examples of the protecting group for the hydroxyl group in general formula 5, acyl groups, benzyl group, silyl groups, trityl group and the like can be referred to. As examples of the acyl group, optionally branched Cl-C6 alkylcarbonyl groups such as ac2tyl group, propionyl group, butyryl group, isopropylcarbonyl group, pentane-carbonyl group and the like; carbonyl groups havingC~-C8 cycloalkyl groups such as cyclopentylcarbonyl group, cyclohexylcarbonyl group, cyclooctylcarbonyl group and the like; benzoyl group; and the like can be referred to. As the silyl groups, t-butyldimethylsilyl group, t butyldiphenylsilyl group, (triphenylmethyl)dimethylsilyl group, methyldiisopropylsilyl group, triisopropylsilyl group and the like can be referred to. As concrete example of the compound, l-amino-2,3-bis(cyclohexane-carbonyloxymethyl)cyclobutane and the like can be referred to.
This compound can be obtained according to the following reaction scheme by using a known compound of the following formula 1 (K. C. Brannock et al., J. Org. Chem., 29, 940 (1964)) as a material.
--1 1 . .
..
~ ` .
.. ~, .
,. o ~ ta ~ :
~. I Z Z
.. . o , ~
; o . :C .,, ~ .....
o~ .~
~ ~ , .
o~ ~o~o ~ w In ~ u~ ~ / ~
~ ~ ~ ~ o " ~, o o + ~
o~o C) ~l ~ ~ .
~ o~o o~o . ;.
' ~' e I _ I ~
-: N O
:j m :c ~! P~
O o 5:
N ~Z O h ~ ~
.
., o~
~ N
:~ m N æ P~ . .
~ . ~
', ~ ~ ~ : ,~ . ~ . .
~U E3 N
X 0~ ~
o o v~/ ~ ~
~ ~ O ~a :.
~ N ~ ~ ` ,' i `
1:~ K ~a a~ a: ~ : i .'.: `
~ ;, :, . .
i . ,` ' ', ~, " ~! , ' ' ' ~ . .
12 ~ 7 1 Thus, 1 was reduced with lithium aluminum hydride and further protected with benzoyl group to synthesi2e 2 (mp 71-71.5C). Then, 2 was treated with -~ p-toluenesulfonic acid in acetone to give 3, and 3 was allowed to react with hydroxylamine to give an oxime 4.
Then, 4 was catalytically reduced in the presence of platinum oxide catalyst to give 5. 5 was a mixture of ` geometric isomers, which can be resolved into 5a and 5b by ; chromatographic treatment.
~BEST MODE FOR CARRYING OUT THE INVENTION]
E~ample 1 Production of Compound 5a (a) 1,1-Diethoxy-trans-2,3-bis(benzoyloxymethyl)cyclo-butane (2~
To a mixture consisting of dry THF (200 m) and ether (200 ml) was suspended 10.23 g (0.27 mole) of lithium aluminum hydride. Diethyl 3,3-diethoxyl-1,2-cyclobutanedicarboxylate (1) (47.15 g, 0.164 mole) was dropwise added to the suspension under ice-cooling. After stirring i~ at room temperature for 2 hours, ethyl acetate (50 ml) and water ~20 ml) were dropwise added thereto under ice-cooling. The resulting gelatinous precipitate -was filtered off and thorouyhly washed with CHC13 (300 ~ `
ml). The filtrate and the washings were united~ washed ;~
with 100 ml of water, dried on anhydrous magnesium sulfate, and then concentrated. The liquid îs subjected to silica gel column chromatography (~6.0 ~ 40 cm) and ,: . .: . , . , ., ., . : . . , . ~" ~, , . -. ; . : : , , .. -7 ~ -1 eluted with O - 60% solution of ethyl acetate in benzene (4 liters). Fractions showing Rf of near 0.36 in thin layer chromatography (benzene : ethyl acetate = 1 : 1) were united, and solvent was distilled off. The residue was dissolved into 150 ml of pyridine, and 32 ml (0.274 mole) of benzoyl chloride was dropwise added thereto under ice-cooling. After allowing it to stand overnight, 10 ml : of water was added and the solvent was distilled off. The residue was dissolved into a mixture of 700 ml of benzene and 700 ml of hexane, washed with 1 liter of water and dried on anhydrous magnesium sulfate, after which the solvent was distilled off. The remaining syrup was crystallized from 300 ml of methanol to give compound (2) as white-colored needle-like crystals (25.50 g, 60%).
mp 71 71.5C.
Anal- Calcd- for C24H286 C~ 69-88; H~ 6-84-`~ Found: C, 70.05; H, 6.91.
MS (m~z): 291 (M - C6H5COO) H-NMR (CDC13) ~:
7.3-8.1 (lOH, m, COC6H5), 4.35-4.65 (4H, m, -CH20-), 3.5 t4H, m, -CH2CH3), 2.77 (lH, ddd, H2), 2.48 ~lH, dd, H4a), 2.37 (lH, m, H3), 1.98 (lH, dd, H4b), 1.2 (6H, m, -CH2CH3).
.
:' ' r J ~ 7 1 (b) trans-2,3-Bis(benzoyloxymethyl)-l-cyclobutanone (3) 2 ~18.0 g, 43.6 mmoles~ is dissolved into 160 ml of acetone. After adding 9.0 g of p-toluenesulfonic acid, it was allowed to stand at room temperature for 2 hours.
5 Then, a liquid mi~ture of 1 liter of hexane and 0.5 liter of benzene was added thareto, and the obtained mi~ture was washed three times with one liter of water and dried on anhydrous magnesium sulfate, and then the solvent was distilled off. 150 ml of he~ane was added to the residue 10 to give compound (3) as white-colored needle-like crystals ~14.01 g, g5%).
~ mp 77.5 - 78C.
;~ Anal- Calcd- for C20Hl~O5 C, 70.99; H~ 5-36-Found: C, 71.03; H, 5.44.
15 MS (m/z): 291 (M - CO).
H-NMR (CDC13) ~: -7.4-8.05 (lOH, m, C6H5C0O3, 4.5-4.65 (4H, m, -CH20-), ~; 3.66 (lH, m, H2), 3.25 (lH, ddd, H4a), 3.07 ~lH, ddd, H4b), ~
2.96 (lH, m, H3~. ;
'~
(c) trans-2,3-Bis~benzoyloxymethyl)-l-cyclobutanone oxime , (4) 3 (14.01 9, 41.4 mmoles) and hydroxylamine hydrochloride (6.4 g, 92 mmoles) were dissolved into 200 ml of pyridine and allowed to stand at 4 overnight. The :-:
: ` ~
- 15 - ~ 7 1 solvent was distilled off and 600 ml of CHC13 was added thereto. The mi~ture was washed three times with 200 ml of water, and dried on anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to an azeotropic distillation with toluene (100 ml, 3 times) and then 150 ml of hexane was added to give compound 4 as white-colored needle-like crystals (13.6 g, 93%)-mp 114 - 115C.
Anal. Calcd. for C20H19O5:
C, 67.98; H, 5.42; N, 3.96.
Found: C, 68.06; H, 5.49; N, 3.93.
MS (m/z~: 353 (M+~, 336 (M - OH).
H-NMR (CDC13) ~:
8.49 and 8.92 (lH, brs, =H-OH), 7.2-8.1 (10H, m, C6H5COO-), 4.4-4.7 (4H, m, -CH2O), 2.6-3.3 (4H, m, H2, H3, H4).
(b) cis-trans- (5b) and trans-trans-1-Amino-2,3-bis-~cyclohe~anecarbonyloxymethyl)cyclobutans (5a) 4 ~1.50 g, 4.25 mmoles) was dissolved into 250 ml of anhydrous ethanol. After adding 0.15 g of platinum oxide, it was stirred at 50C overnight while introducing hydrogen gas. Then, a check of the reaction by TLC tcolor development by ninhydrin) revealed formation of two products different in Rf from each other. After distilling .: ' ' . ' ' ' ' '. . . . ,., ' , : ~; . ;
' . . .' ' ' : . ' ' , ' ' , '. . " . ' , ' . , . . ' ' ' ~ ~
~ ,. ' , : , , .
. . ' ' , . . .
,~'' ' . " . ' ' . '., ' 1 off the solvent, the residue was dissolved into a small quantity of chloroform, loaded on a silica gel chromato-graphy (~1.5 ~ 30 cm) and eluted with chloroform containing 0-10% of ethanol (1.5 liters~ to fractionate them. By distilling off solvent from the first fraction, 5b (420.0 mg, 28.2 %) was obtained as a caramel.
MS (m/z): 352 (M+ + 1~.
1H - NMR (CDC13) ~:
4.36-4.14 (2H, each dd, 2-CH2O-), 4.08 (2H, d, 3-CH2O-), 3.69 (lH, q, Hl), 2.0-2.5 ~4H, m, H2, H3, H4), 1.2-2.0 (m, -OCOCH(-)(CH~)5-x2).
After distilling off solvent from the second ` 15 fraction, the residue was crystallized from ethyl acetate to give 5a (301.6 mg, 20.26~ as white-colored crystals.
mp 100 - 103C. ;~
MS (m/z) 352 (M+ + 1).
Anal. Calcd- for C20H33N4- 2H2 C, 67.65; H, 9.48; N, 3.g4.
Found: C, 67.47; H, 9.54; N, 3.49.
336 (M - OH).
. 1 H-NMR (CDC13) 4.08-4.15 (2H, m, 2-CH2O~
4.08 (4H, m, 3-CH2O-), :
3.13 (lH, q, Hl), :
.:
. ~ .
L~
2.24-2.37 (4H, m, H4, -OCOCH(-) (C::H2~5x2), 1.98-2.05 (2H, m, H2, H3), ;; 1.18-1. 97 (m, -OCOCH(-) ~CH2)5~2).
Example 2 Production of Carboxethanocin A (Compound 9) 9-[trans-trans-2,3-Bis~hydroxymethyl)cyclobutyl~adenine (9) 8 (109 mg, 0.23 mmole) was dissolved in 1 ml of methanol. After adding 1 ml of lN solution of NaOH, the mixture is stirred at room temperature for 30 minutes. It ; was neutralized with acetic acid and the solvent was distilled off. The resulting residue was dissolved in a small quantity of water and adsorbed on active charcoal (3 g) column. After washin~ with 100 ml of water, it was eluted with 200 ml of ethanol-water-concentrated ammonia (10 : 9 : 1). The solvent was distilled off, and the ;
residue was dissolved in a small quantity of water, and the solution was filtered on cellulose powder to remove the carbon. Then, solvent was distilled off to give a solid. It was crystallized from ethanol to give compound 9 as white-colored crystals (42 mg, 73%).
` ~ 20 mp 190.5 ~ 192C.
W ~ma~ (H2O) 261 nm, ~max (pH 1) 2~3-5 nm~
max (pH 1 1) 261 nm, MS ~m/z): 249 (M ).
lH-NMR ~CDC13) ~:
; 8.24 ~lH, s, H8~, .
, . : , , , . ~
: ............... : . . : . :
- 18 ~ v~ ~ ~ 7 1 8.13 (lH, s, H2), 7020 ~2H, s, NH2), 2'- and 3'-CH20H (4.65, lH, brs and 4.79, lH, brs), 4.63 (lH, ddd, Hl'), 3.52 (4H, s-liks, 2'- and 3'-CH20H), 2.78 (lH, m, H2'~, 2.43 (lH, ddd, H4', a), 2.24 (lH, ddd, H4', b), :
2.10 (lH, m, H3'). ~ -I~he starting compound 8 was obtained according to the following method by using as a material compound 5a :
obtained by the method of E~ample 1.
(a~ N6-[trans-trans-2,3-Bis(cyclohexanecarbonyloxy-I5 methyl)cyclobutyl]-5,6-diamino-4-chloropyridine (6) ::-5a (209 mg, 0.60 mmole) was dissolved in 3.5 ml of l-butanol. After adding 0.57 ml of triethylamine and ;
S-amino-4,6-dichloropyrimidine (294 mg, 1.79 mmoles) ::~
thereto, the mixture was heated under ref lu2 overnight.
After ascertaining the reaction by TLC, solvent was distilled off, and the residue was dissolved in benzene, .
subjected to silica gel column chromatography ~2.2 x 28 ~ cm) and eluted with (0.9 liter~ containing 0-50% of ethyl ; acetate. The fractions containing the product were :~:
united, from which the solvent was distilled off. Thus, the compound 6 was obtained as a caramel (2~0 mg, 84.2%).
~i : -- 19 --1W ~ma~ (MeOH) 298 5 nm, ~ma~ (pH 1) 314.5 nm, max (pH 1 1) 299 nm MS (m/z): 479, 480 (M+ + 1).
AND INTERMEDIATE THEREFOR
'' .:' ~' 1 [TECHNICAL FIELD] -This invention relates to a process for producing carboxetanocin G or carboxetanocin A having an antiviral activity and expected to be useful as an antiviral agent, and to an intermediate for them.
.
[P~IOR ART]
: Ever since the isolation of the carbocyclic analogues of naturally occurring adenosine such as aristelomycin ~T. Kusaka et al., J. Antibiot., 21, 255 (1968)) and nepranocin (S. Yaginuma et al., ibid., 34, 359 (1981)), the syntheses of carbocyclic analogues of purine and pyrimidine nucleoside have been watched with interest.
.
CH ~ CH
HO ~ ~ HO ~
OH OH OH OH
Aristelomycin Nepranocin Oxetanocin A, recently reported, is a novel oxetanosyl-N-glycoside isolated from culture product of Bacillus , .. . .. . . . . .
( l megaterium, and it has antiviral, antitumorigenic and antibacterial activaties (N. Shimada et al., J. Antibiot., .
39, 1623 (1986)).
NH2 ' ' / CH
~~ " - ', ''` ' ~/
`' CH2 \
, ` Oxetanocin A
In view of the above, the present inventors :~
~5 attempted to synthesize other carbocyclic analogues of oxetanocin A. : -, [DISCLOSURE OF THE INVENTION]
: :
:In the first aspact, this invention relates to a process for synthesizing carboxetanocin G represented by formula (II):
' . ~ . . ~ ~ ................... . ..
- .
O
`' ' ~t/ :., ~ HOH C ~ ~
.1~ ~',',';.' 1 characterized by treating a compound represented by ` ~:
formula (I):
~ .
i3,~ , ?~.
Cl N
H2N ,,.,~. , 1 ~ COOH C I I ~
", ' H2C ;`
: with an alkali hydroxide, followed by treating it with an acid.
: 5 In~the second aspect, thls invent1on relates to `~
a process or producing carboxetanocin A represented by '~
formula 9~
.',','....
'' : '',,, NH
. .
HOCH N ~ N 9 ;',, ~ "~ ' .~ y ., I
:1 ~ H2H
.
:i :
~ .
1 characterized by treating a compound represented by formula 8~
' -NH2 :;
COOCH~ N ~N j 8 ~ ` .
~ ~ ~ A
~ CH20CO ~) ' `~ with an alkali hydro~ide.
, In the third aspect, this invention relates to cyclobutane derivatives represented by formula 5:
: P-OCH2 ': y CH O P ~ :
.
~ 5 ~
1 wherein P is a protecting group for hydroxyl group, which are useful as an intermediate for these carboxetanocins.
In the first place, the first aspect of this invention will be explained.
In the invention of the first aspect, as the alkali hydroxide, alkali metal hydroxides such as sodium ;~ hydroxide, lithium hydroxide, potassium hydroxide and the like can be referred to, for example. Among them, sodium hydroxide is general and preferable. As its amount, an i 10 amount of 1.5 ml or above, for example, as lN solution per 0.44 mmole o the compound of formula (I) is sufficient.
Usually it is used in an amount of about 2 ml. Though the reaction temperature is not limited, room temperature is sufficient.
A solvent for the compound of formula (I) is not limited, so far as it dissolves the compound of formula .
(X) and excercises no adverse influence on the reaction. ,~, -Dio~ane and the like are referred to, for example.
As the acid, mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and the like can be referred to, among which hydrochloric acid is general and~
preferable. Although its amount varies depending on the . .
amount of the alkali hydroxide used in the preceding step, it is usually 2 ml or above as lN hydrochloric acid per 0.44 mmole of the compound of formula (I), and an amount of about 3 ml is practically advisable.
The reaction with acid can be carried out by adding an acid to the reaction liquid obtained by --' ,`'.
. .
~o ~ L;~-~,3 ~ ~ i ; 1 the above-mentioned reaction with sodium hydroxide, pre~erably concentrating it, and then making the reaction progress preferably in the neighborhood of boiling point of the solvent.
: 5 After completion of the reaction, purification -~
treatment such as chromatographic treatment, recrystal-lization or the like is carried out, whereby ; carboxethanocin G represented by formula (II) is obtained.
The compound of formula (I) used as starting material can be obtained according to the following reaction scheme from a compound of formula 5a mentioned below.
:
, .
'`
, .
:.":. . ~,:
- 7 ~ t~
" U ',",',:'':.
`J ~
~ ~v 3 $ g o , .~,` , ~ ~
.,,. ~V . -- ~.
o\~
Z 4 o ~z ~ ~ o ~ ~ b E
` ~ 8 ~ .
~N~3 b o ~ 0~o ~ ~
N ~ ~z ~ N ~
~ ' Z Z~ o ~ b EQ'~
; O m ~ ' '', o~ ~:
r~
, . , . , ~ , . . .. .. ; . . ~ : ' - .. . .
J
1 Next the second aspect of this invention will be explained.
As the alkali hydroxide used in the second aspect of this invention, the same ones as mentioned in ; 5 the first aspect of this invention can be referred to, among which sodium hydro~ide is general and preferable.
As its amount, an amount of 0.7 ml or above as lN aqueous solution per 0.23 mmole of the compound of formula 8 is sufficient. Usually, it is used in an amount of about 1 ml. The reaction temperature is not limited, and room temperature is sufficient.
As a sol~ent for the reaction, any solvent may be used without limitation so far as it dissolves the compound of formula 8 and exercises no adverse influence on the reaction. As examples of the solvent, alcohols such as methanol, ethanol and the like can be referred to.
After completion of the reaction, purification treatment such as column treatment, recrystallization or the like is carried out, whereby carboxethanocin A
represented by formula 9 is obtained.
~ The compound of formula 8 can be obtained i according to the following reaction scheme by using a compound of formula 5a mentioned below as a starting material.
g ~ 7 ,:, . ~ -. .
~ .`
. ~
o~o o ~
~æ Q
æ~z v u~
o o c o o .. o\O
, ~ ~o r, .~.-~ l o\o æ ~ ~ 1 ,` ,, ~ ~r -~ ~ ~ .
~ Q ~z Q
o o z\ o ~ ot~S -~ ~ < ~
cN~
O ~ O ' ~' O O
- 10- 2~V~
1 Next, the third aspect of this invention will be explained.
In the third aspect of this invention, as examples of the protecting group for the hydroxyl group in general formula 5, acyl groups, benzyl group, silyl groups, trityl group and the like can be referred to. As examples of the acyl group, optionally branched Cl-C6 alkylcarbonyl groups such as ac2tyl group, propionyl group, butyryl group, isopropylcarbonyl group, pentane-carbonyl group and the like; carbonyl groups havingC~-C8 cycloalkyl groups such as cyclopentylcarbonyl group, cyclohexylcarbonyl group, cyclooctylcarbonyl group and the like; benzoyl group; and the like can be referred to. As the silyl groups, t-butyldimethylsilyl group, t butyldiphenylsilyl group, (triphenylmethyl)dimethylsilyl group, methyldiisopropylsilyl group, triisopropylsilyl group and the like can be referred to. As concrete example of the compound, l-amino-2,3-bis(cyclohexane-carbonyloxymethyl)cyclobutane and the like can be referred to.
This compound can be obtained according to the following reaction scheme by using a known compound of the following formula 1 (K. C. Brannock et al., J. Org. Chem., 29, 940 (1964)) as a material.
--1 1 . .
..
~ ` .
.. ~, .
,. o ~ ta ~ :
~. I Z Z
.. . o , ~
; o . :C .,, ~ .....
o~ .~
~ ~ , .
o~ ~o~o ~ w In ~ u~ ~ / ~
~ ~ ~ ~ o " ~, o o + ~
o~o C) ~l ~ ~ .
~ o~o o~o . ;.
' ~' e I _ I ~
-: N O
:j m :c ~! P~
O o 5:
N ~Z O h ~ ~
.
., o~
~ N
:~ m N æ P~ . .
~ . ~
', ~ ~ ~ : ,~ . ~ . .
~U E3 N
X 0~ ~
o o v~/ ~ ~
~ ~ O ~a :.
~ N ~ ~ ` ,' i `
1:~ K ~a a~ a: ~ : i .'.: `
~ ;, :, . .
i . ,` ' ', ~, " ~! , ' ' ' ~ . .
12 ~ 7 1 Thus, 1 was reduced with lithium aluminum hydride and further protected with benzoyl group to synthesi2e 2 (mp 71-71.5C). Then, 2 was treated with -~ p-toluenesulfonic acid in acetone to give 3, and 3 was allowed to react with hydroxylamine to give an oxime 4.
Then, 4 was catalytically reduced in the presence of platinum oxide catalyst to give 5. 5 was a mixture of ` geometric isomers, which can be resolved into 5a and 5b by ; chromatographic treatment.
~BEST MODE FOR CARRYING OUT THE INVENTION]
E~ample 1 Production of Compound 5a (a) 1,1-Diethoxy-trans-2,3-bis(benzoyloxymethyl)cyclo-butane (2~
To a mixture consisting of dry THF (200 m) and ether (200 ml) was suspended 10.23 g (0.27 mole) of lithium aluminum hydride. Diethyl 3,3-diethoxyl-1,2-cyclobutanedicarboxylate (1) (47.15 g, 0.164 mole) was dropwise added to the suspension under ice-cooling. After stirring i~ at room temperature for 2 hours, ethyl acetate (50 ml) and water ~20 ml) were dropwise added thereto under ice-cooling. The resulting gelatinous precipitate -was filtered off and thorouyhly washed with CHC13 (300 ~ `
ml). The filtrate and the washings were united~ washed ;~
with 100 ml of water, dried on anhydrous magnesium sulfate, and then concentrated. The liquid îs subjected to silica gel column chromatography (~6.0 ~ 40 cm) and ,: . .: . , . , ., ., . : . . , . ~" ~, , . -. ; . : : , , .. -7 ~ -1 eluted with O - 60% solution of ethyl acetate in benzene (4 liters). Fractions showing Rf of near 0.36 in thin layer chromatography (benzene : ethyl acetate = 1 : 1) were united, and solvent was distilled off. The residue was dissolved into 150 ml of pyridine, and 32 ml (0.274 mole) of benzoyl chloride was dropwise added thereto under ice-cooling. After allowing it to stand overnight, 10 ml : of water was added and the solvent was distilled off. The residue was dissolved into a mixture of 700 ml of benzene and 700 ml of hexane, washed with 1 liter of water and dried on anhydrous magnesium sulfate, after which the solvent was distilled off. The remaining syrup was crystallized from 300 ml of methanol to give compound (2) as white-colored needle-like crystals (25.50 g, 60%).
mp 71 71.5C.
Anal- Calcd- for C24H286 C~ 69-88; H~ 6-84-`~ Found: C, 70.05; H, 6.91.
MS (m~z): 291 (M - C6H5COO) H-NMR (CDC13) ~:
7.3-8.1 (lOH, m, COC6H5), 4.35-4.65 (4H, m, -CH20-), 3.5 t4H, m, -CH2CH3), 2.77 (lH, ddd, H2), 2.48 ~lH, dd, H4a), 2.37 (lH, m, H3), 1.98 (lH, dd, H4b), 1.2 (6H, m, -CH2CH3).
.
:' ' r J ~ 7 1 (b) trans-2,3-Bis(benzoyloxymethyl)-l-cyclobutanone (3) 2 ~18.0 g, 43.6 mmoles~ is dissolved into 160 ml of acetone. After adding 9.0 g of p-toluenesulfonic acid, it was allowed to stand at room temperature for 2 hours.
5 Then, a liquid mi~ture of 1 liter of hexane and 0.5 liter of benzene was added thareto, and the obtained mi~ture was washed three times with one liter of water and dried on anhydrous magnesium sulfate, and then the solvent was distilled off. 150 ml of he~ane was added to the residue 10 to give compound (3) as white-colored needle-like crystals ~14.01 g, g5%).
~ mp 77.5 - 78C.
;~ Anal- Calcd- for C20Hl~O5 C, 70.99; H~ 5-36-Found: C, 71.03; H, 5.44.
15 MS (m/z): 291 (M - CO).
H-NMR (CDC13) ~: -7.4-8.05 (lOH, m, C6H5C0O3, 4.5-4.65 (4H, m, -CH20-), ~; 3.66 (lH, m, H2), 3.25 (lH, ddd, H4a), 3.07 ~lH, ddd, H4b), ~
2.96 (lH, m, H3~. ;
'~
(c) trans-2,3-Bis~benzoyloxymethyl)-l-cyclobutanone oxime , (4) 3 (14.01 9, 41.4 mmoles) and hydroxylamine hydrochloride (6.4 g, 92 mmoles) were dissolved into 200 ml of pyridine and allowed to stand at 4 overnight. The :-:
: ` ~
- 15 - ~ 7 1 solvent was distilled off and 600 ml of CHC13 was added thereto. The mi~ture was washed three times with 200 ml of water, and dried on anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was subjected to an azeotropic distillation with toluene (100 ml, 3 times) and then 150 ml of hexane was added to give compound 4 as white-colored needle-like crystals (13.6 g, 93%)-mp 114 - 115C.
Anal. Calcd. for C20H19O5:
C, 67.98; H, 5.42; N, 3.96.
Found: C, 68.06; H, 5.49; N, 3.93.
MS (m/z~: 353 (M+~, 336 (M - OH).
H-NMR (CDC13) ~:
8.49 and 8.92 (lH, brs, =H-OH), 7.2-8.1 (10H, m, C6H5COO-), 4.4-4.7 (4H, m, -CH2O), 2.6-3.3 (4H, m, H2, H3, H4).
(b) cis-trans- (5b) and trans-trans-1-Amino-2,3-bis-~cyclohe~anecarbonyloxymethyl)cyclobutans (5a) 4 ~1.50 g, 4.25 mmoles) was dissolved into 250 ml of anhydrous ethanol. After adding 0.15 g of platinum oxide, it was stirred at 50C overnight while introducing hydrogen gas. Then, a check of the reaction by TLC tcolor development by ninhydrin) revealed formation of two products different in Rf from each other. After distilling .: ' ' . ' ' ' ' '. . . . ,., ' , : ~; . ;
' . . .' ' ' : . ' ' , ' ' , '. . " . ' , ' . , . . ' ' ' ~ ~
~ ,. ' , : , , .
. . ' ' , . . .
,~'' ' . " . ' ' . '., ' 1 off the solvent, the residue was dissolved into a small quantity of chloroform, loaded on a silica gel chromato-graphy (~1.5 ~ 30 cm) and eluted with chloroform containing 0-10% of ethanol (1.5 liters~ to fractionate them. By distilling off solvent from the first fraction, 5b (420.0 mg, 28.2 %) was obtained as a caramel.
MS (m/z): 352 (M+ + 1~.
1H - NMR (CDC13) ~:
4.36-4.14 (2H, each dd, 2-CH2O-), 4.08 (2H, d, 3-CH2O-), 3.69 (lH, q, Hl), 2.0-2.5 ~4H, m, H2, H3, H4), 1.2-2.0 (m, -OCOCH(-)(CH~)5-x2).
After distilling off solvent from the second ` 15 fraction, the residue was crystallized from ethyl acetate to give 5a (301.6 mg, 20.26~ as white-colored crystals.
mp 100 - 103C. ;~
MS (m/z) 352 (M+ + 1).
Anal. Calcd- for C20H33N4- 2H2 C, 67.65; H, 9.48; N, 3.g4.
Found: C, 67.47; H, 9.54; N, 3.49.
336 (M - OH).
. 1 H-NMR (CDC13) 4.08-4.15 (2H, m, 2-CH2O~
4.08 (4H, m, 3-CH2O-), :
3.13 (lH, q, Hl), :
.:
. ~ .
L~
2.24-2.37 (4H, m, H4, -OCOCH(-) (C::H2~5x2), 1.98-2.05 (2H, m, H2, H3), ;; 1.18-1. 97 (m, -OCOCH(-) ~CH2)5~2).
Example 2 Production of Carboxethanocin A (Compound 9) 9-[trans-trans-2,3-Bis~hydroxymethyl)cyclobutyl~adenine (9) 8 (109 mg, 0.23 mmole) was dissolved in 1 ml of methanol. After adding 1 ml of lN solution of NaOH, the mixture is stirred at room temperature for 30 minutes. It ; was neutralized with acetic acid and the solvent was distilled off. The resulting residue was dissolved in a small quantity of water and adsorbed on active charcoal (3 g) column. After washin~ with 100 ml of water, it was eluted with 200 ml of ethanol-water-concentrated ammonia (10 : 9 : 1). The solvent was distilled off, and the ;
residue was dissolved in a small quantity of water, and the solution was filtered on cellulose powder to remove the carbon. Then, solvent was distilled off to give a solid. It was crystallized from ethanol to give compound 9 as white-colored crystals (42 mg, 73%).
` ~ 20 mp 190.5 ~ 192C.
W ~ma~ (H2O) 261 nm, ~max (pH 1) 2~3-5 nm~
max (pH 1 1) 261 nm, MS ~m/z): 249 (M ).
lH-NMR ~CDC13) ~:
; 8.24 ~lH, s, H8~, .
, . : , , , . ~
: ............... : . . : . :
- 18 ~ v~ ~ ~ 7 1 8.13 (lH, s, H2), 7020 ~2H, s, NH2), 2'- and 3'-CH20H (4.65, lH, brs and 4.79, lH, brs), 4.63 (lH, ddd, Hl'), 3.52 (4H, s-liks, 2'- and 3'-CH20H), 2.78 (lH, m, H2'~, 2.43 (lH, ddd, H4', a), 2.24 (lH, ddd, H4', b), :
2.10 (lH, m, H3'). ~ -I~he starting compound 8 was obtained according to the following method by using as a material compound 5a :
obtained by the method of E~ample 1.
(a~ N6-[trans-trans-2,3-Bis(cyclohexanecarbonyloxy-I5 methyl)cyclobutyl]-5,6-diamino-4-chloropyridine (6) ::-5a (209 mg, 0.60 mmole) was dissolved in 3.5 ml of l-butanol. After adding 0.57 ml of triethylamine and ;
S-amino-4,6-dichloropyrimidine (294 mg, 1.79 mmoles) ::~
thereto, the mixture was heated under ref lu2 overnight.
After ascertaining the reaction by TLC, solvent was distilled off, and the residue was dissolved in benzene, .
subjected to silica gel column chromatography ~2.2 x 28 ~ cm) and eluted with (0.9 liter~ containing 0-50% of ethyl ; acetate. The fractions containing the product were :~:
united, from which the solvent was distilled off. Thus, the compound 6 was obtained as a caramel (2~0 mg, 84.2%).
~i : -- 19 --1W ~ma~ (MeOH) 298 5 nm, ~ma~ (pH 1) 314.5 nm, max (pH 1 1) 299 nm MS (m/z): 479, 480 (M+ + 1).
- 5 ~ MR ( CDC 13 ~ 8:
8.05 (lH, S, H2), 5.0-5.2 (2H, m, N4-H, Hl'~, 4O05-4~25 (4H, m, 2'- and 3'-CH2O-), 3.4 (2H, s, -NH2). `~
.. ! , .' ` 10 (b) 9-[trans-trans-2, 3-BiS (cyclohexanecarbonylo~ymethyl)-cyclobutyl]-6-chloropurine (7) To 6 (220.9 mg, 0.46 mmole) were added 2 ml of triethyl orthoformate and one drop of concentrated hydro-chloric acid, and the mixture was allowed to react at room i 15 temperature for 5 hours. The reac:tion was stopped by adding triethylamine and the solvent was distilled off.
The residue was dissolved into 50 ml of CHC13, and then the solution was washed with 20 ml of water and dried on ., - . .
~ anhydrous magnesium sulfate. Then, the solution was con-. .
20 centrated, subjected to silica gel column chromatography (~2.0 x 42 cm) and eluted with chloroform ~1.5 liters) r containing 0-10~ of ethanol. The fractions containing the ;~ product were united, from which the solvent was distilled - off to give the compound 7 as a caramel (174 mg, 77.2%~.
W: ~max ~MeOH) 266 nm, ` max (pH 1) 266 nm, max (pH 1 1) 265 nm, , , . -. .
.
,. ~ , .. .. . . . . ,. . . . :
:1 :
;
1 MS (m~z): 488, 480 (M ).
H-NMR (CDC13) ~-B.75 (lH, s, H8), 8.18 (lH, s, H2), 4.6-4.95 (lH, m, Hl'), ;
4.2-4.3 (4H, m, 2' and 3'-CH20-).
. ~"';'.
(c) 9-[trans-trans-2,3-Bis(cyclohexanecarbonyloxymethyl)-cyclobutyl]adenine (8) 7 (150 mg, 0.31 mmole) was charged into a 10 pressure-resistant vessel. While cooling it in acetone- `
dry ice, about 1 ml of liquid ammonia was added, and `
reacted at 40C overnight. Then, the ammonia was vaporized off carefully, the residue was dissolved in ethanol, and the solvent was distilled off. After dissolving the residue in 30 ml of CHC13, the solution was washed with 15 ml of water and dried on anhydrous magnesium sulfat . The solution was concentrated, ;
subjected to silica gel column chromatography (~1.6 x 14 cm), and eluted with chloroform (300 ml) containing 0 -10~ of ethanol. The fractions containing the product were united, the solvent was distilled off, and the residue was crystallized from a small quantity of methanol to give the compound 8 as white-colored crystals (127 mg, 28%j.
W : ~ma~ tMeOH) 262 nm, max (pH 1) 26l nm, max (pH 1 1) 262 nm, ' .,'''''' `
., :.
'~' , `:
2 ~ r~
l~S (m/z): 469 (M+).
1H-NMR (CDC13) ~:
8.75 (1H, S, H8~, 8.18 (lH, s, H2), 4.6-4.95 ~lH, m, Hl'), 4.2-4.3 (4H, m, 2' and 3'-CH2O-).
E~ample 3 Production of CarboYetanocin G ~Compound II) 1) Starting compound (I) (220 mg, 0.44 mmole) was dissolved in 15 ml of dioxane. After adding 2 ml of lN solution of sodium hydro~ide and 2 ml of water, the mi~ture was stirred at room temperature for 3 hours.
2) After addinq 3 ml of lN hydrochloric acid, the mixture was concentrated to 7 ml. The concentrate was washed three times with 3 ml of chloroform and heated under reflux for lO hours.
3~ Ater cooling it, it was subjected to active :
charcoal column chromatography. A~ter washing the column with 70 ml of water, the adsorbed matter was eluted with 150 ml of a mixture of ethanol-water-concentrated ammonia 20 ~(10 : 9 : l).
4) After concentrating the eluted solution, carbon was removed by the use of cellulose powder.
Recrystallization from a small quantity of water gave 71 mg (0.27 mmole, 61%) of th~ objective compound (II) as white-colored needle-like crystals.
~,, ' ~. ' .' ' '; " ' ' ' ~ ' "" ~ '":
.
- 22 - ~ 7 1 mp 269 - 270C
max (0.05N HCl) 258 nm, 279 nm ~max (H2O) 253 nm, 270 nm (sh~, ~ma~ (0.05N NaOH) 269 nm, 255 nm (sh3.
Proton-NMR (DMSO-d6):
7.84 ~lH, s, H8), ;
8.05 (lH, S, H2), 5.0-5.2 (2H, m, N4-H, Hl'~, 4O05-4~25 (4H, m, 2'- and 3'-CH2O-), 3.4 (2H, s, -NH2). `~
.. ! , .' ` 10 (b) 9-[trans-trans-2, 3-BiS (cyclohexanecarbonylo~ymethyl)-cyclobutyl]-6-chloropurine (7) To 6 (220.9 mg, 0.46 mmole) were added 2 ml of triethyl orthoformate and one drop of concentrated hydro-chloric acid, and the mixture was allowed to react at room i 15 temperature for 5 hours. The reac:tion was stopped by adding triethylamine and the solvent was distilled off.
The residue was dissolved into 50 ml of CHC13, and then the solution was washed with 20 ml of water and dried on ., - . .
~ anhydrous magnesium sulfate. Then, the solution was con-. .
20 centrated, subjected to silica gel column chromatography (~2.0 x 42 cm) and eluted with chloroform ~1.5 liters) r containing 0-10~ of ethanol. The fractions containing the ;~ product were united, from which the solvent was distilled - off to give the compound 7 as a caramel (174 mg, 77.2%~.
W: ~max ~MeOH) 266 nm, ` max (pH 1) 266 nm, max (pH 1 1) 265 nm, , , . -. .
.
,. ~ , .. .. . . . . ,. . . . :
:1 :
;
1 MS (m~z): 488, 480 (M ).
H-NMR (CDC13) ~-B.75 (lH, s, H8), 8.18 (lH, s, H2), 4.6-4.95 (lH, m, Hl'), ;
4.2-4.3 (4H, m, 2' and 3'-CH20-).
. ~"';'.
(c) 9-[trans-trans-2,3-Bis(cyclohexanecarbonyloxymethyl)-cyclobutyl]adenine (8) 7 (150 mg, 0.31 mmole) was charged into a 10 pressure-resistant vessel. While cooling it in acetone- `
dry ice, about 1 ml of liquid ammonia was added, and `
reacted at 40C overnight. Then, the ammonia was vaporized off carefully, the residue was dissolved in ethanol, and the solvent was distilled off. After dissolving the residue in 30 ml of CHC13, the solution was washed with 15 ml of water and dried on anhydrous magnesium sulfat . The solution was concentrated, ;
subjected to silica gel column chromatography (~1.6 x 14 cm), and eluted with chloroform (300 ml) containing 0 -10~ of ethanol. The fractions containing the product were united, the solvent was distilled off, and the residue was crystallized from a small quantity of methanol to give the compound 8 as white-colored crystals (127 mg, 28%j.
W : ~ma~ tMeOH) 262 nm, max (pH 1) 26l nm, max (pH 1 1) 262 nm, ' .,'''''' `
., :.
'~' , `:
2 ~ r~
l~S (m/z): 469 (M+).
1H-NMR (CDC13) ~:
8.75 (1H, S, H8~, 8.18 (lH, s, H2), 4.6-4.95 ~lH, m, Hl'), 4.2-4.3 (4H, m, 2' and 3'-CH2O-).
E~ample 3 Production of CarboYetanocin G ~Compound II) 1) Starting compound (I) (220 mg, 0.44 mmole) was dissolved in 15 ml of dioxane. After adding 2 ml of lN solution of sodium hydro~ide and 2 ml of water, the mi~ture was stirred at room temperature for 3 hours.
2) After addinq 3 ml of lN hydrochloric acid, the mixture was concentrated to 7 ml. The concentrate was washed three times with 3 ml of chloroform and heated under reflux for lO hours.
3~ Ater cooling it, it was subjected to active :
charcoal column chromatography. A~ter washing the column with 70 ml of water, the adsorbed matter was eluted with 150 ml of a mixture of ethanol-water-concentrated ammonia 20 ~(10 : 9 : l).
4) After concentrating the eluted solution, carbon was removed by the use of cellulose powder.
Recrystallization from a small quantity of water gave 71 mg (0.27 mmole, 61%) of th~ objective compound (II) as white-colored needle-like crystals.
~,, ' ~. ' .' ' '; " ' ' ' ~ ' "" ~ '":
.
- 22 - ~ 7 1 mp 269 - 270C
max (0.05N HCl) 258 nm, 279 nm ~max (H2O) 253 nm, 270 nm (sh~, ~ma~ (0.05N NaOH) 269 nm, 255 nm (sh3.
Proton-NMR (DMSO-d6):
7.84 ~lH, s, H8), ;
6.40 (2H, s, 2-NH2), 4.68 (lH, t, 2~CH2OH), 4.62 (lH, t, 2-CH2OH), 3.50 (4H, m, 2- and 3-CH2OH), 2.69 (lH, m, H-2), 2.35 (lH, m, H-3), 2.04 (2H, m, H-4).
The starting compound ~I) could be obtained according to the following method by using as a material compound 5a obtained by the method of Example 1.
'~ ' ' (a) 2-Amino-6-~2,3-bis(cyclohexylcarbonyloxymethyl)-cyclobutylamino]pyrimidine (19) 1) Starting compound 5a (431 mg, 1.23 mmoles~
and 2-amino-4,6-dichloropyrimidine (202 mg, 1.23 mmoles) . , .
were dissolved in a mixture of n-butanol Ç5 ml), methanol ;;
S0.5 ml) and triethylamine (1.5 ml), and heated under reflux for 11 hours.
2) After cooling the mixture, the solvent was ~ ~
25 dis~iIled off. The residue was dissolved in 30 ml of ~-chloroform, washed twice with 10 ml of water and dried on magnesium sulfate.
~'.
1 3~ The solution was concentrated, subjected to silica gel column chromatography (~3.4 ~ 30 cm) and eluted with 0 - 20% solution of AcOEt in CHC13 ~1 liter).
4) The fractions containing the product were united and the solvent was distilled off to give 383 mg ~0.88 mmole, 71%~ of compound 19 as a syrup. -W : ~max (0.05N HCl) 286 nm max (MeOH) 289 nm, ~max (0.05N NaOH) 289 nm-Proton-NMR (CDC13):
5.84 (lH, s, H5), 5.27 ~2H, s, 2-NH2), 3.9-4.6 (5H, m, Hl', 2- and 3-CH2O-), 1.0-2.6 (ca. 26H, H2', H3', H4~, OCOC6H~
(b) 2-Amino-4-chloro-5-(4-chlorophenyl)azo-6-[2,3-bis-(cyclohexylcarbonyloxymethyl)--cyclobutylamino]-pyrimidine (20) 1) p-Chloroaniline (828 mg) was dissolved into a mixture of 4 ml of concentrated hydrochloric acid and 10.8 ml of water.
2) Sodium nitrite (471 mg) was dissolved into 4.1 ml of water.
3) The solution obtained in 2~ was portionwise dropped to the solution obtained in 1) under ice-cooling.
' . ' ~ .. . ~ - ~ . , - , - . . .. . . :.
:, , :. . .. , - . . .
. ~ . : : : . .
., . . . ~ , .. : . ,, . . ~ - ~
The starting compound ~I) could be obtained according to the following method by using as a material compound 5a obtained by the method of Example 1.
'~ ' ' (a) 2-Amino-6-~2,3-bis(cyclohexylcarbonyloxymethyl)-cyclobutylamino]pyrimidine (19) 1) Starting compound 5a (431 mg, 1.23 mmoles~
and 2-amino-4,6-dichloropyrimidine (202 mg, 1.23 mmoles) . , .
were dissolved in a mixture of n-butanol Ç5 ml), methanol ;;
S0.5 ml) and triethylamine (1.5 ml), and heated under reflux for 11 hours.
2) After cooling the mixture, the solvent was ~ ~
25 dis~iIled off. The residue was dissolved in 30 ml of ~-chloroform, washed twice with 10 ml of water and dried on magnesium sulfate.
~'.
1 3~ The solution was concentrated, subjected to silica gel column chromatography (~3.4 ~ 30 cm) and eluted with 0 - 20% solution of AcOEt in CHC13 ~1 liter).
4) The fractions containing the product were united and the solvent was distilled off to give 383 mg ~0.88 mmole, 71%~ of compound 19 as a syrup. -W : ~max (0.05N HCl) 286 nm max (MeOH) 289 nm, ~max (0.05N NaOH) 289 nm-Proton-NMR (CDC13):
5.84 (lH, s, H5), 5.27 ~2H, s, 2-NH2), 3.9-4.6 (5H, m, Hl', 2- and 3-CH2O-), 1.0-2.6 (ca. 26H, H2', H3', H4~, OCOC6H~
(b) 2-Amino-4-chloro-5-(4-chlorophenyl)azo-6-[2,3-bis-(cyclohexylcarbonyloxymethyl)--cyclobutylamino]-pyrimidine (20) 1) p-Chloroaniline (828 mg) was dissolved into a mixture of 4 ml of concentrated hydrochloric acid and 10.8 ml of water.
2) Sodium nitrite (471 mg) was dissolved into 4.1 ml of water.
3) The solution obtained in 2~ was portionwise dropped to the solution obtained in 1) under ice-cooling.
' . ' ~ .. . ~ - ~ . , - , - . . .. . . :.
:, , :. . .. , - . . .
. ~ . : : : . .
., . . . ~ , .. : . ,, . . ~ - ~
7 ~ ~
1 4) Compound (19) (1.22 g, 2.55 mmoles~ was dissolved in 4.8 ml of acetic acid. A solution of 6.15 g of sodium acetate trihydrates in 5.9 ml of water was added thereto.
5~ The solution of 3) was portionwise dropped into 4) (over a period of about 30 minutes).
6) The resulting mixture was stirred at room temperature for one day, and the solvent was distilled off. The residue was dissolved in 100 ml of chloroform and the solution was washed twice with 50 ml of saturated aqueous solution of sodium bicarbonate, washed with 50 ml of water, and dried on magnesium sulfate.
7) The solution was concentrated, subjected to silica gel column chromatography (~2.5 x 35 cm) and eluted with 0 - 25% solution of AcOEt in benzane.
1 4) Compound (19) (1.22 g, 2.55 mmoles~ was dissolved in 4.8 ml of acetic acid. A solution of 6.15 g of sodium acetate trihydrates in 5.9 ml of water was added thereto.
5~ The solution of 3) was portionwise dropped into 4) (over a period of about 30 minutes).
6) The resulting mixture was stirred at room temperature for one day, and the solvent was distilled off. The residue was dissolved in 100 ml of chloroform and the solution was washed twice with 50 ml of saturated aqueous solution of sodium bicarbonate, washed with 50 ml of water, and dried on magnesium sulfate.
7) The solution was concentrated, subjected to silica gel column chromatography (~2.5 x 35 cm) and eluted with 0 - 25% solution of AcOEt in benzane.
8) The fractions containing the product are united and the solvent was distilled off to give 930 mg (1.51 mmoles, 59%) of compound ~20) as yellow-colored -;
crystals. ;~
mp 161 - 163C.
Anal. Calcd- for C30H38cl2N6o4: -C; 58.35, H; 6.20, N; 13.61.
Found: C; 58.28, H; 6.17, N; 13.70. -~ -; W : ~ma~ (0.05N HCl) 382 nm, 283 nm, ;
~max (MeOH) 390 nm, 283 nm, ;
~max (0.05N NaOH) 390 nm, 281 nm. -Protor.-NMR (CDC13):
phenyl proton (7.71, 2H, d and 7.44, 2H, d~
L~
1 6.15 (2H, ~rs, 2-NH2), 3-CH2O- (4.73, lH, q, and 3.96, lH, q), 4.15 (2H, m, 2-CH2O-), 0.9-2.7 (ca. 26H, H2', H3', H4', OCOC6Hll).
(c) 2,5-Diamino-4-chloro-6-[2,3-bis(cyclohexyl-carbonyloxymethyl)cyclobutylamino-pyrimidine (21) 1) Compound (20) (500 mg, 0.81 mmole) and zinc (590 mg) were suspended in a mi~ture of 2.7 ml of acetic acid, 67 ml of ethanol and 5 ml of water and heated under reflux for 1.5 hours.
2) After coolin~, the insoluble matter was filtered off, and the solvent was distilled off. The residue was subjected to an azeotropic distillation with 10 ml of benzene and then dissolved into 10 ml of benzene.
3) The solution was subjected to silica gel `
column chromatography (~2.6 x 25 cm) and eluted with 0 -50% solution of AcOEt in benzene (1.2 liters).
4) The fractions containing the product were united and the solvent was distilled off to give 222 mg `~
20 ~0.45 mmole, 56%) of compound (21) as white-colored crystals.
: :
mp 106 - 109C.
; Anal. Calcd. for C24H36CIN5O4:
C;~58.35, H; 7.35, N; 14.18.
Found: C; 58.53, H; 7O40~ N; 14.32.
. : . ;: . ~ . . -2~D~90 max (0.05N HCl) 312 nm ~max (MeOH) 308 nm, max (0-05N NaOH~ 305 nm Proton-NMX (CDC13):
5.67 ~lH, brs, 5-NH~, 4.88 (2H, brs, 2-NH2), 3-CH2O- (4.50, lH, q ans 4.0S, lH, q), 4.20 (lH, m, Hl'), 4.08-4.16 (2H, m, 2-CH2O-3, 2.2 (2H, brs, S-NH2), 1.15-2.5 (ca. 26H, H2', H3', ~4 ! ~ OCOC6H
(d~ 2-~mino-6-chloro-9-~2,3-bis(cyclohexylcarbonyloxy- ~ `~
methyl)cyclobutyl]purine (I) 1) Compound (21) (390 mg" 0.79 mmole) was dissolved in 3.6 ml of triethyl orl:hoformate. After 0.5 ml of concentrated hydrochloric ac;d was dropped to the solution, the mixture is stirred at: room temperature for 3 ~-hours.
2) After neutralizing the mixture with triethylamine, the solvent was distilled off, and the residue was dissolved into 30 ml of chloroform, washed ,.
with 20 ml of water and dried on magnesium sulfate.
3) It was subjected to silica gel column chromatography ~2.1 x 30 cm) and eluted with 0 - 2.5%
solution of EtOH in chloroform.
8) The fractions containing the product were united and the solvent was distilled off to qive the '~ ""' . ' ~ .
,..,. ~ .
~3~
1 compound (I) (220 mg, 0.44 mmole, 55%) as white-colored crystals.
mp 127 - 134C.
25 34 5O4 0.5H2O:
C; 58.52, H; 7.88, N; 13.65.
Found: C; 58.57, H; 6.44, N; 13.24.
W : ~max (0-05 NHCl~ 292 nm, (MeOH) 292 nm~
max Proton-NMR (CDC13):
2-NH2 (9.51, lH, d, J=10.16 and 8.14, lH, J=10.71), ;
8nO4 (lH, s, H8), 4.60 (5H, q-like, -CH2O-, Hl'), -~
1.1-3.1 (ca. 26H, H2', H3', , OCOC6Hll).
[IN2USTRIAL APPLICABILITY]
As for the carboxethanocin A and carbo~ethanocin G obtained according to the process of this invention, their efficacies were reported at the 5th meeting of the International AIDS Society held in Motreal, Canada, on June 4-9, 1989, and they are e~pected to be useful as an antiviral agent such as therapeutic drug of AIDS, etc.
:, ,, , , : . ,. , . ,,i . . . :
, . , , , , , . .. . . . . : : ~
crystals. ;~
mp 161 - 163C.
Anal. Calcd- for C30H38cl2N6o4: -C; 58.35, H; 6.20, N; 13.61.
Found: C; 58.28, H; 6.17, N; 13.70. -~ -; W : ~ma~ (0.05N HCl) 382 nm, 283 nm, ;
~max (MeOH) 390 nm, 283 nm, ;
~max (0.05N NaOH) 390 nm, 281 nm. -Protor.-NMR (CDC13):
phenyl proton (7.71, 2H, d and 7.44, 2H, d~
L~
1 6.15 (2H, ~rs, 2-NH2), 3-CH2O- (4.73, lH, q, and 3.96, lH, q), 4.15 (2H, m, 2-CH2O-), 0.9-2.7 (ca. 26H, H2', H3', H4', OCOC6Hll).
(c) 2,5-Diamino-4-chloro-6-[2,3-bis(cyclohexyl-carbonyloxymethyl)cyclobutylamino-pyrimidine (21) 1) Compound (20) (500 mg, 0.81 mmole) and zinc (590 mg) were suspended in a mi~ture of 2.7 ml of acetic acid, 67 ml of ethanol and 5 ml of water and heated under reflux for 1.5 hours.
2) After coolin~, the insoluble matter was filtered off, and the solvent was distilled off. The residue was subjected to an azeotropic distillation with 10 ml of benzene and then dissolved into 10 ml of benzene.
3) The solution was subjected to silica gel `
column chromatography (~2.6 x 25 cm) and eluted with 0 -50% solution of AcOEt in benzene (1.2 liters).
4) The fractions containing the product were united and the solvent was distilled off to give 222 mg `~
20 ~0.45 mmole, 56%) of compound (21) as white-colored crystals.
: :
mp 106 - 109C.
; Anal. Calcd. for C24H36CIN5O4:
C;~58.35, H; 7.35, N; 14.18.
Found: C; 58.53, H; 7O40~ N; 14.32.
. : . ;: . ~ . . -2~D~90 max (0.05N HCl) 312 nm ~max (MeOH) 308 nm, max (0-05N NaOH~ 305 nm Proton-NMX (CDC13):
5.67 ~lH, brs, 5-NH~, 4.88 (2H, brs, 2-NH2), 3-CH2O- (4.50, lH, q ans 4.0S, lH, q), 4.20 (lH, m, Hl'), 4.08-4.16 (2H, m, 2-CH2O-3, 2.2 (2H, brs, S-NH2), 1.15-2.5 (ca. 26H, H2', H3', ~4 ! ~ OCOC6H
(d~ 2-~mino-6-chloro-9-~2,3-bis(cyclohexylcarbonyloxy- ~ `~
methyl)cyclobutyl]purine (I) 1) Compound (21) (390 mg" 0.79 mmole) was dissolved in 3.6 ml of triethyl orl:hoformate. After 0.5 ml of concentrated hydrochloric ac;d was dropped to the solution, the mixture is stirred at: room temperature for 3 ~-hours.
2) After neutralizing the mixture with triethylamine, the solvent was distilled off, and the residue was dissolved into 30 ml of chloroform, washed ,.
with 20 ml of water and dried on magnesium sulfate.
3) It was subjected to silica gel column chromatography ~2.1 x 30 cm) and eluted with 0 - 2.5%
solution of EtOH in chloroform.
8) The fractions containing the product were united and the solvent was distilled off to qive the '~ ""' . ' ~ .
,..,. ~ .
~3~
1 compound (I) (220 mg, 0.44 mmole, 55%) as white-colored crystals.
mp 127 - 134C.
25 34 5O4 0.5H2O:
C; 58.52, H; 7.88, N; 13.65.
Found: C; 58.57, H; 6.44, N; 13.24.
W : ~max (0-05 NHCl~ 292 nm, (MeOH) 292 nm~
max Proton-NMR (CDC13):
2-NH2 (9.51, lH, d, J=10.16 and 8.14, lH, J=10.71), ;
8nO4 (lH, s, H8), 4.60 (5H, q-like, -CH2O-, Hl'), -~
1.1-3.1 (ca. 26H, H2', H3', , OCOC6Hll).
[IN2USTRIAL APPLICABILITY]
As for the carboxethanocin A and carbo~ethanocin G obtained according to the process of this invention, their efficacies were reported at the 5th meeting of the International AIDS Society held in Motreal, Canada, on June 4-9, 1989, and they are e~pected to be useful as an antiviral agent such as therapeutic drug of AIDS, etc.
:, ,, , , : . ,. , . ,,i . . . :
, . , , , , , . .. . . . . : : ~
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for synthesizing carboxethanocin G
represented by formula (II):
(II) characterized by treating a compound represented by formula (I):
(I) with an alkali hydroxide and subsequently treating it with an acid.
represented by formula (II):
(II) characterized by treating a compound represented by formula (I):
(I) with an alkali hydroxide and subsequently treating it with an acid.
2. A process according to Claim 1, wherein said alkali hydroxide is sodium hydroxide and said acid is hydrochloric acid.
3. A process according to Claim 2, wherein said sodium hydroxide is used in an amount of 1.5 ml or above as lN aqueous solution and said hydrochloric acid is used in an amount of 2 ml or above as lN hydrochloric acid, both per 0.44 mmole of the compound of formula (I).
4. A process for producing carboxethanocin A
represented by formula 9:
9 characterized by treating a compound represented by formula 8:
8 with an alkali hydroxide.
represented by formula 9:
9 characterized by treating a compound represented by formula 8:
8 with an alkali hydroxide.
5. A process according to Claim 4, wherein said alkali hydroxide is sodium hydroxide.
6. A process according to Claim 5, wherein said sodium hydroxide is used in an amount of 0.7 ml or above as lN aqueous solution per 0.23 mmole of the compound of formula 8.
7. A cyclobutane derivative represented by formula 5:
5 wherein P is a protecting group for hydroxyl group.
5 wherein P is a protecting group for hydroxyl group.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP02-003436 | 1990-01-12 | ||
| JP2003436A JP2898326B2 (en) | 1990-01-12 | 1990-01-12 | Synthetic method of carbooxetanosin G |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2049047A1 true CA2049047A1 (en) | 1991-07-13 |
Family
ID=11557308
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002049047A Abandoned CA2049047A1 (en) | 1990-01-12 | 1990-02-27 | Process for producing carboxetanocin g or a intermediate therefor |
Country Status (3)
| Country | Link |
|---|---|
| JP (1) | JP2898326B2 (en) |
| CA (1) | CA2049047A1 (en) |
| WO (1) | WO1991010665A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000069806A1 (en) * | 1999-05-17 | 2000-11-23 | Lonza Ag | Method for producing chiral amines |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8520553D0 (en) * | 1985-08-16 | 1985-09-25 | Glaxo Group Ltd | Chemical compound |
-
1990
- 1990-01-12 JP JP2003436A patent/JP2898326B2/en not_active Expired - Lifetime
- 1990-02-27 CA CA002049047A patent/CA2049047A1/en not_active Abandoned
- 1990-02-27 WO PCT/JP1990/000235 patent/WO1991010665A1/en active Application Filing
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000069806A1 (en) * | 1999-05-17 | 2000-11-23 | Lonza Ag | Method for producing chiral amines |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2898326B2 (en) | 1999-05-31 |
| WO1991010665A1 (en) | 1991-07-25 |
| JPH03215486A (en) | 1991-09-20 |
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