CA1076566A - Processes for the preparation of 3',4'-dideoxykanamycin b - Google Patents
Processes for the preparation of 3',4'-dideoxykanamycin bInfo
- Publication number
- CA1076566A CA1076566A CA337,672A CA337672A CA1076566A CA 1076566 A CA1076566 A CA 1076566A CA 337672 A CA337672 A CA 337672A CA 1076566 A CA1076566 A CA 1076566A
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- Prior art keywords
- kanamycin
- cyclohexylidene
- formula
- penta
- derivative
- Prior art date
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-
- 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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Abstract
TITLE OF INVENTION:
New Processes for the Preparation of 3',4'-Dideoxykanamycin B
ABSTRACT OF THE DISCLOSURE:
New routes are provided for the synthesis of 3',4'-dideoxykanamycin B which is effective in inhibiting kanamycin-resistant organisms from kanamycin B through new intermediate, of which a fundamental process comprises a new reaction of a 3',4'-epoxy derivative of amino- and hydroxyl-protected kanamycin B with a xanthate to form a corresponding 3',4'-dideoxy-3'-eno derivative followed by removal of the amino- and hydroxyl-protecting groups thereof and by hydrogenation of the resulting 3',4'-dideoxy-3'-eno-kanamycin B. A 3',4'-episulfide deriv-ative corresponding to the 3',4'-epoxy derivative which is formed as second product in the reaction of 3',4'-epoxy derivative with xanthate is also used as intermediate for the preparation of 3',4'-dideoxykanamycin B.
New Processes for the Preparation of 3',4'-Dideoxykanamycin B
ABSTRACT OF THE DISCLOSURE:
New routes are provided for the synthesis of 3',4'-dideoxykanamycin B which is effective in inhibiting kanamycin-resistant organisms from kanamycin B through new intermediate, of which a fundamental process comprises a new reaction of a 3',4'-epoxy derivative of amino- and hydroxyl-protected kanamycin B with a xanthate to form a corresponding 3',4'-dideoxy-3'-eno derivative followed by removal of the amino- and hydroxyl-protecting groups thereof and by hydrogenation of the resulting 3',4'-dideoxy-3'-eno-kanamycin B. A 3',4'-episulfide deriv-ative corresponding to the 3',4'-epoxy derivative which is formed as second product in the reaction of 3',4'-epoxy derivative with xanthate is also used as intermediate for the preparation of 3',4'-dideoxykanamycin B.
Description
765~
BACKGROUND OF THE INVENTION:
This invention relates to new routes for the synthesis of 3',4'-dideoxykanamycin B which is anti-bacterial against a variety of gram-positive and gram-negative bacteria and particularly effective in inhibiting kanamycin-resistant organisms such as kanamycin-resistant Staphylococci and kanamycin-resistant Escherichia coli.
DESCRIPTION OF THE PRIOR ART:
3'g4'-Dideoxykanamycln B having the structure:
.~ .
5 ~ ~ ~H2 . 4' ~ ~ 1 o ~ l :~ . 6"
, HOCH2 j 4" ~ O~
,` H~éV
:
- .
` 10 has hitherto been prepared by a method comprising pro-:. tecting~the five amino groups and all or a part of the hydroxyl groups other than 3'- and 4'-hydroxyl groups -of kanamycin B by a conventional method, sulfonylating the 3'- and 4'-hydroxyl groups to afford a deri~ative having 3'- and 4'-disulfonic ester groups~ removing the ::
.: 31_ and 4'-disulfonic ester groups by known methods to : give a 3',4'-unsaturated compound, reducing the 3'~4'-. 2 ','- ~ ~
. . :
:
.~ 6~
unsaturated compound and removing the residual protecting groups. The known method requires nine steps from kana-mycin B to 3',4' dideoxykanamycin B (see British Patent Specification No. 1,349,302). Further, the method re-quires the use of sodium iodide and zinc powder in large amounts in the step for removing the 3' and 4'-disulfonic ester groups, thus involving questions of iodine resources and of environmental pollution resulting from disposal of by-products. Therefore, the development of new, more advantageous method for synthesis of 3',4'-dideoxykanamycin B has eagerly been desired from the industrial point o~
view.
i SUMMARY OF THE INVENTION:
It is the primary object of this invention to pro-vide some new routes for the synthetic preparation of 3', 4'-dideoxykanamycin B which are advantageous over the `I prior art in that thèy do not use an alkali metal bromide ¦ or iodide and zinc powder, but use other reagents o~ less expenses. All the new processes originate from kanamycin B as in the prior art but pass through a new route of reaction.
According to a first aspect of this inventiona therefore, there is provided a process for the preparation of 3',4'-dideoxykanamycin B or its acid ad~ition salts and mt~dia~es t~hereof o~rising one or mDre of the ~olla~ng steps:
(1) treating with a xanthate a 3',4'-epoxy derivative of an amino- and hydroxyl-protected kanamycin B of the formula:
, ~65~6 .
CH2~HCOOR NHCOOR
~ ~ HCOOR
o-~l ~f ~HCOOR
OCH2¦ O (I) Z/~l wherein ~ represents a hydrogen atom or an alkyl or aryl group, Z represents an alkylidene,~arylidene~ cyclohexyli-dene or tetrahydropyranylidene group and the: 3',4'-epoxy . group is in ~- or ~-position whereby to form a 3',4'-: ~dideoxy-3'-eno-1canamycln B derivatlve o~ the formula:
~ ~ CH2~HCOORI ~COOR
L ~
~HCOOR
Z~
~ ' ' ' ,.
' ~ ., ' " ~ '' , ~ '' .' . , : ' ~ ' ', ~
~7~5~6 wherein R and Z have the same meaning as defined above together with a 3',4'-episulfido-kanamycin B derivative of the formula:
CH2 i~HCOOR NHCOOR
~- ~
NHcoox ~ /
/~ (III) OH
, i~ wherein R and Z have the same meaning as defined above and the 3',4'-episulfide group is in ~- or ~-position;
(2~j isolating the 3'~4'-dldeoxy--3'-eno-kanamycin:B
:~ derivative from the reaction mixture;
, . .
. (3) removing the amino-protecting groups -COOR and hydroxyl-protecting group Z of the 3',4'-dideoxy-3' eno derivative thus isolated in a conventional manner to . form 3',4'-dideoxy-3'-eno-kanamycin B of the formula:
,; .
,, ' ~'.
~ .
.,~
~L~7~:i5~6 CH2NH2 ~H2 N~z XOC~2 ~ O (IV) ~0~
HO ~
o~ .
and (4) hydrogenating the compound thus formed in a conventional manner to form 3i,4'-dideoxykanamycin B, and, if desired, converting the compound thus ~ormed into an acid addition salt thereof.
The step (1) of the first aspect process of this invention, that is the treatment of a 3',4'-epoxy deriv-ative of the formula (I) in either a- or ~-form with a xanthate, may be effected in an organic solvent, pref~
erably at a temperature of 50~100C. The organic solvent may preferably be a lower alkanol such as methanol and ethanol. The xanthate to be used for this treatment may be those of the formula R'OCSSMe where R' is a lower alkyl group, Me is an alkali metal such as sodium or potassium. Generally, this reaction gives a 3',4'-dideoxy-3'-eno derivative of the formula (II) as a first product in admixture with a 3',4'-episulfide derivative of the formula (III) as a second product after washing .
,. .: . : , . . , . ~
" ' ~ ' ~ . ' ' .,, 7~S66 the reaction mixture with water, recovering the solvent by distillation and concentrating the residue to dryness.
The mechanism of reaction between the 3',4'-epoxy derivative of the formula (I) and the xanthate has not yet been made clear, but a presumable possibility is that the conversion of 3',4'-epoxy derivative into correspond-ing 3',41-dideoxy-3'-eno derivative of the formula (II) proceeds via corresponding 3',4'-episulfide derivative of the formula (III).
; 10 The isolation of the first and second products of the step (1) from each other, i.e. the step (2) of the first aspect process, may be effected, preferably by chromatography, for example silica-gel thin layer chromato-; graphy in a usual manner, for example using a mixture ~ (e.g. 1:1 by ~olume) of carbon tetrachloride and acetone .,; .
as developer.
The step (3) of the first aspect process of this -invention for the removal of the amino-protecting groups -COOR and hydroxyl-protecting group Z may be carried out in a usual manner. For example, the removal of the hydroxyl protecting group Z may first be effected by a mild hydrolysis with a dilute hydrochloric acid or an aqueous acetic acid and then the amino_protecting groups may be removed by a hydrolysis with barium hydroxide or by hydrogenolysis in the presence of a palladium catalyst.
The step (4) of the first aspect process, that is the hydrogenation step, may be carried out in a known manner.
Thus, a catalytic reduction with hydrogen in the presence of a known hydrogenation catalyst comprising a platinum group metal such as platinum or palladium may preferably ,;
'' ' ~6 be applicable to the step (4). Raney nickel catalyst may also be used for this purpose.
The first aspect process of this invention is advantageous over the prior ar~ process above-mentioned in that the formation of 3',4'-unsaturation can be achieved without relying on the reaction involving the use o~ an alkali bromide or iodide and zinc powder;
~ as the final intermediate compound which is to be converted to the desired product, 3',4'-dideoxykanamycin B, in the last step, 3',4'-dideoxy-3'-eno-kanamycin B, i.e. the compound of the formula (IV) free from any protecting group can be obtained;
- in the last step, the catalytic hydrogenation can be achieved relatively easily with much less impurities derived from reagents used, so that the purification of the final product is required only to a less extent than in the prior art process wherein the step for removin~ amino- and hydroxyl-protecting groups is carried~fout after the step for the hydrogenation.
It will be appreciated, however, that the order of the steps (3) and (4) of the first aspect process of this invention can be reversed, if desired, to follow the known order adopted by the prior art process.
The final product, 3',4'-dideoxykanamycin B in free -~ base form, may be converted, if desired, to an acid addition salt derived from an inorganic or organic acid. For example, , 5~
sulfate of 3',4'-dideoxykanamycin B may be obtained by adding dilute sulfuric acid to an aqueous solution of the free base to adjust the pH value to 6.8, treating the solution with decoloring carbong filtering the solution and freeze-drying the filtrate.
We have further found that the 3',4'-episulfide derivative of the formula (III) which is formed as second product in the step (l) of the first aspect process of this invention is also useful as intermediate for the j 10 preparation o~ 3',4'~dideoxykanamycin B. Our discovery in this respect is that there are two routes for converting the 3',4'-episulfide derivative of the formula (III) to a known useful intermediate for the preparation of 3'g 4'-dideoxykanamycin B; the first route is to treat the 3',4'-episulfide derivative with an acid to form 3',4'-dideoxy-3'-eno-kanamycin B of the formula (I~) and the second route ls to treat the 3',4'-episulfide derivative with hydrazine or Raney nickeI to form a 3',4'-dideoxy-3'-eno-kanamycin B derivative of the formula ~II).
According to a second aspect process of this ; ~ invention, therefore, we provide a process for the prepara-tion of 3',4'-dideoxykanamycin B or its acid addition saltsand inb~diates thereof o~rising one or more of the foll~ steps;
(1) treating with a xanthate a 3',4'-epoxy derivative of an amlno- and hydroxyl-protected kanamycin B Or the lormula:
, , 7~66 CH2~XCOOR ¦ NHCOOR
HCOOR
~0~ ~
~HCOOR
OCH2 O (I) :
Z/~/ ~ ~
,'~ ' .
~: ' ~ ' :
wherein R represents a hydrogen atom or an alkyl or aryl group, Z represents an alkylidene, arylidene~ cyclohexylidene or tetrahydropyranylidene group and the 3',4'-epoxy group is in ~- or~ ~-position whereby to form a 3',4'-ep:isul~ido~
kanamycin B derivative of the formula~
, . .
.
NHCOOR
XCOOR ~;
' S~ O ~ ` ~
j NHCOOR
/. ~ ., :
/
~ (III) ." \o~ `
` OH
: - .
,. .
. .
' :' , :. ' :.
5~
wherein R and Z have the same meaning as defined above and the 3'34'-episulfide group is in ~- or ~-position together with a 3',4'-dideoxy-3'-eno-kanamycin B derivative of the formula.
' .
~2NHCOOR ¦ NHCOOR
~ NHCOOR
'~ O ~
NHCOOR
OC~ O (II) z\/i~
OH
.
wherein R and Z have the same meaning as defined abovej
BACKGROUND OF THE INVENTION:
This invention relates to new routes for the synthesis of 3',4'-dideoxykanamycin B which is anti-bacterial against a variety of gram-positive and gram-negative bacteria and particularly effective in inhibiting kanamycin-resistant organisms such as kanamycin-resistant Staphylococci and kanamycin-resistant Escherichia coli.
DESCRIPTION OF THE PRIOR ART:
3'g4'-Dideoxykanamycln B having the structure:
.~ .
5 ~ ~ ~H2 . 4' ~ ~ 1 o ~ l :~ . 6"
, HOCH2 j 4" ~ O~
,` H~éV
:
- .
` 10 has hitherto been prepared by a method comprising pro-:. tecting~the five amino groups and all or a part of the hydroxyl groups other than 3'- and 4'-hydroxyl groups -of kanamycin B by a conventional method, sulfonylating the 3'- and 4'-hydroxyl groups to afford a deri~ative having 3'- and 4'-disulfonic ester groups~ removing the ::
.: 31_ and 4'-disulfonic ester groups by known methods to : give a 3',4'-unsaturated compound, reducing the 3'~4'-. 2 ','- ~ ~
. . :
:
.~ 6~
unsaturated compound and removing the residual protecting groups. The known method requires nine steps from kana-mycin B to 3',4' dideoxykanamycin B (see British Patent Specification No. 1,349,302). Further, the method re-quires the use of sodium iodide and zinc powder in large amounts in the step for removing the 3' and 4'-disulfonic ester groups, thus involving questions of iodine resources and of environmental pollution resulting from disposal of by-products. Therefore, the development of new, more advantageous method for synthesis of 3',4'-dideoxykanamycin B has eagerly been desired from the industrial point o~
view.
i SUMMARY OF THE INVENTION:
It is the primary object of this invention to pro-vide some new routes for the synthetic preparation of 3', 4'-dideoxykanamycin B which are advantageous over the `I prior art in that thèy do not use an alkali metal bromide ¦ or iodide and zinc powder, but use other reagents o~ less expenses. All the new processes originate from kanamycin B as in the prior art but pass through a new route of reaction.
According to a first aspect of this inventiona therefore, there is provided a process for the preparation of 3',4'-dideoxykanamycin B or its acid ad~ition salts and mt~dia~es t~hereof o~rising one or mDre of the ~olla~ng steps:
(1) treating with a xanthate a 3',4'-epoxy derivative of an amino- and hydroxyl-protected kanamycin B of the formula:
, ~65~6 .
CH2~HCOOR NHCOOR
~ ~ HCOOR
o-~l ~f ~HCOOR
OCH2¦ O (I) Z/~l wherein ~ represents a hydrogen atom or an alkyl or aryl group, Z represents an alkylidene,~arylidene~ cyclohexyli-dene or tetrahydropyranylidene group and the: 3',4'-epoxy . group is in ~- or ~-position whereby to form a 3',4'-: ~dideoxy-3'-eno-1canamycln B derivatlve o~ the formula:
~ ~ CH2~HCOORI ~COOR
L ~
~HCOOR
Z~
~ ' ' ' ,.
' ~ ., ' " ~ '' , ~ '' .' . , : ' ~ ' ', ~
~7~5~6 wherein R and Z have the same meaning as defined above together with a 3',4'-episulfido-kanamycin B derivative of the formula:
CH2 i~HCOOR NHCOOR
~- ~
NHcoox ~ /
/~ (III) OH
, i~ wherein R and Z have the same meaning as defined above and the 3',4'-episulfide group is in ~- or ~-position;
(2~j isolating the 3'~4'-dldeoxy--3'-eno-kanamycin:B
:~ derivative from the reaction mixture;
, . .
. (3) removing the amino-protecting groups -COOR and hydroxyl-protecting group Z of the 3',4'-dideoxy-3' eno derivative thus isolated in a conventional manner to . form 3',4'-dideoxy-3'-eno-kanamycin B of the formula:
,; .
,, ' ~'.
~ .
.,~
~L~7~:i5~6 CH2NH2 ~H2 N~z XOC~2 ~ O (IV) ~0~
HO ~
o~ .
and (4) hydrogenating the compound thus formed in a conventional manner to form 3i,4'-dideoxykanamycin B, and, if desired, converting the compound thus ~ormed into an acid addition salt thereof.
The step (1) of the first aspect process of this invention, that is the treatment of a 3',4'-epoxy deriv-ative of the formula (I) in either a- or ~-form with a xanthate, may be effected in an organic solvent, pref~
erably at a temperature of 50~100C. The organic solvent may preferably be a lower alkanol such as methanol and ethanol. The xanthate to be used for this treatment may be those of the formula R'OCSSMe where R' is a lower alkyl group, Me is an alkali metal such as sodium or potassium. Generally, this reaction gives a 3',4'-dideoxy-3'-eno derivative of the formula (II) as a first product in admixture with a 3',4'-episulfide derivative of the formula (III) as a second product after washing .
,. .: . : , . . , . ~
" ' ~ ' ~ . ' ' .,, 7~S66 the reaction mixture with water, recovering the solvent by distillation and concentrating the residue to dryness.
The mechanism of reaction between the 3',4'-epoxy derivative of the formula (I) and the xanthate has not yet been made clear, but a presumable possibility is that the conversion of 3',4'-epoxy derivative into correspond-ing 3',41-dideoxy-3'-eno derivative of the formula (II) proceeds via corresponding 3',4'-episulfide derivative of the formula (III).
; 10 The isolation of the first and second products of the step (1) from each other, i.e. the step (2) of the first aspect process, may be effected, preferably by chromatography, for example silica-gel thin layer chromato-; graphy in a usual manner, for example using a mixture ~ (e.g. 1:1 by ~olume) of carbon tetrachloride and acetone .,; .
as developer.
The step (3) of the first aspect process of this -invention for the removal of the amino-protecting groups -COOR and hydroxyl-protecting group Z may be carried out in a usual manner. For example, the removal of the hydroxyl protecting group Z may first be effected by a mild hydrolysis with a dilute hydrochloric acid or an aqueous acetic acid and then the amino_protecting groups may be removed by a hydrolysis with barium hydroxide or by hydrogenolysis in the presence of a palladium catalyst.
The step (4) of the first aspect process, that is the hydrogenation step, may be carried out in a known manner.
Thus, a catalytic reduction with hydrogen in the presence of a known hydrogenation catalyst comprising a platinum group metal such as platinum or palladium may preferably ,;
'' ' ~6 be applicable to the step (4). Raney nickel catalyst may also be used for this purpose.
The first aspect process of this invention is advantageous over the prior ar~ process above-mentioned in that the formation of 3',4'-unsaturation can be achieved without relying on the reaction involving the use o~ an alkali bromide or iodide and zinc powder;
~ as the final intermediate compound which is to be converted to the desired product, 3',4'-dideoxykanamycin B, in the last step, 3',4'-dideoxy-3'-eno-kanamycin B, i.e. the compound of the formula (IV) free from any protecting group can be obtained;
- in the last step, the catalytic hydrogenation can be achieved relatively easily with much less impurities derived from reagents used, so that the purification of the final product is required only to a less extent than in the prior art process wherein the step for removin~ amino- and hydroxyl-protecting groups is carried~fout after the step for the hydrogenation.
It will be appreciated, however, that the order of the steps (3) and (4) of the first aspect process of this invention can be reversed, if desired, to follow the known order adopted by the prior art process.
The final product, 3',4'-dideoxykanamycin B in free -~ base form, may be converted, if desired, to an acid addition salt derived from an inorganic or organic acid. For example, , 5~
sulfate of 3',4'-dideoxykanamycin B may be obtained by adding dilute sulfuric acid to an aqueous solution of the free base to adjust the pH value to 6.8, treating the solution with decoloring carbong filtering the solution and freeze-drying the filtrate.
We have further found that the 3',4'-episulfide derivative of the formula (III) which is formed as second product in the step (l) of the first aspect process of this invention is also useful as intermediate for the j 10 preparation o~ 3',4'~dideoxykanamycin B. Our discovery in this respect is that there are two routes for converting the 3',4'-episulfide derivative of the formula (III) to a known useful intermediate for the preparation of 3'g 4'-dideoxykanamycin B; the first route is to treat the 3',4'-episulfide derivative with an acid to form 3',4'-dideoxy-3'-eno-kanamycin B of the formula (I~) and the second route ls to treat the 3',4'-episulfide derivative with hydrazine or Raney nickeI to form a 3',4'-dideoxy-3'-eno-kanamycin B derivative of the formula ~II).
According to a second aspect process of this ; ~ invention, therefore, we provide a process for the prepara-tion of 3',4'-dideoxykanamycin B or its acid addition saltsand inb~diates thereof o~rising one or more of the foll~ steps;
(1) treating with a xanthate a 3',4'-epoxy derivative of an amlno- and hydroxyl-protected kanamycin B Or the lormula:
, , 7~66 CH2~XCOOR ¦ NHCOOR
HCOOR
~0~ ~
~HCOOR
OCH2 O (I) :
Z/~/ ~ ~
,'~ ' .
~: ' ~ ' :
wherein R represents a hydrogen atom or an alkyl or aryl group, Z represents an alkylidene, arylidene~ cyclohexylidene or tetrahydropyranylidene group and the 3',4'-epoxy group is in ~- or~ ~-position whereby to form a 3',4'-ep:isul~ido~
kanamycin B derivative of the formula~
, . .
.
NHCOOR
XCOOR ~;
' S~ O ~ ` ~
j NHCOOR
/. ~ ., :
/
~ (III) ." \o~ `
` OH
: - .
,. .
. .
' :' , :. ' :.
5~
wherein R and Z have the same meaning as defined above and the 3'34'-episulfide group is in ~- or ~-position together with a 3',4'-dideoxy-3'-eno-kanamycin B derivative of the formula.
' .
~2NHCOOR ¦ NHCOOR
~ NHCOOR
'~ O ~
NHCOOR
OC~ O (II) z\/i~
OH
.
wherein R and Z have the same meaning as defined abovej
(2) isolating the 3',4'-episulfido-kanamycin B derivative from the reaction mixture;
(3) treating the 3~,4'-episulfide derivative thus isolated with an acid t.o form 3',4'-dideoxy-3'-eno-kanamycin B of the formula:
~ ~7~5~i6 .
C~I2N~I2 ~2 NIIZ
HOCH2 o ( IV ) '~ ,/~ 0 / :
¦~: N~32 ~V
HO \~/
` ~ : OH
.
.' .
and (4) hydrogenating the compound thus formed in a conventional manner to form 3',4'~dideoxykanamycin B;
and, if desired, converting the compound thus~formed into an acid additlon salt thereof.
The steps (1)~,(2) and (4) of the second~aspect process o~ this invention correspond to the steps (l), (2) and (4) of~the first aspect process as above-mentioned~?
respectively. ~ ~ -:
The step (3~ of the second aspect process~ i.e. the treatment of the 3',4'-eplsulfide der1vative of the formula :
(III) with an acid may preferably be carried out i~ a lower ~
. .
alkanol such as methanol and ethanol using a hydrohalogenic acid such as concentrated hydrochloric acid and hydrobromic acid. In general ? however ? a non-oxidizing mineral acid, for example sulfurlc acid, may be used for this treatment.
Preferably, the treatment may be carried out at a tempera-ture of 0~30C.
.' - 12 - ~
;
.:
.. . . . . .
. , . , , ' , . ' .
. . ' . '.
~7~
According to a third aspect process of this inven-tion, there is provided a process for the preparation of 3',4'-dideoxykanamycin B or its acid addition salts and int~E~a*es thereof ~x~rismg one or more of the foll~ng steps:
(1) treating with a xanthate a 3',4' epoxy derivative of an amino- and hydroxyl-protected kanamycin B of the formula:
;
CH2l~XCOOR ¦ NHCOOR
~0 ~NHCOOR
~ ~\~
~ICOOR
OC~I2 o (I) Z~
. , .
OH.
wherein R represents a hydrogen atom or an alkyl or aryl group and Z represents an alkylidene; arylidene, cyclo-hexylidene or tetrahydropyranylidene group whereby to form a 3'g4'-episulfido-kanamycin B.derivative of:the fo~mula:
~ 65~6 CB2~HCOOR I~HCOOR
Coo~ ~
NHCOOR
OCH2 ( III ) . .
Z/~ \l / :
HCOOR /V
` 'H' OH
. ~
wherein R and Z have the same meaning as defined above and 3 t, 4'-episulfide group is in a- or ~-position together : with a 3',4'-dideoxy-3'-eno-kanamycin ~ derivative of the formula: :
:: :
CH2NHCOOR j ~IHCOOR
o~
NHCOOR
( II ) z/l/~
OH
.
.. : .
~765i~
wherein R and Z have the same meaning as defined above;
(2) treating the reaction mixture from the step (1) with hydrazine or Raney nickel to convert the 3',4'-episulfide derivative of the formula (III) into a further amount of the 3',4'-dideoxy-3'-eno-kanamycin B derivative of the formula (II) above;
(3) removin~ the amino-protecting groups -COOR and hydroxyl-; protecting group Z of the 3',4'-dideoxy-3'-eno derivative thus formed in a conventional manner to form 3',4'-dideoxy-3'-eno-kanamycin B of the formula:
' ~u\
; / (IV~
HOCH2 o/
,'`,' ' '~ ~/
' ' HO ~
OH
' and (4) hydrogenating the compound thus formed in a con-ventional manner to form 3',4'-dideoxykanamycin B; and, if desired, converting the compound thus formed into an acid addition salt thereof.
The steps (1),(3) and (4) of the third aspect process of this invention correspond to the steps (1),(3) and (4) of the first aspect process as above-mentioned, respectively.
65~ii6 In the step (2) of the third aspect process, the treatment with hydrazine may preferably be effected in a lower alkanol such as methanol and ethanol using hydrazine, particularly in the form of hydrate NH2NH2-H20~ at room temperatures, usually 15~-25C. The amount of hydrazine to be used may preferably be about 10~30 moles per mole of the compound of the formula (III). The treatment with Raney nickel, if adopted for the step (2), may preferably .~
be carried out by dissolving the compound of the formula -(III) in a lower alkanol, for example methanol, adding Raney nickel to:the:solution in an appropriate amount, for .example threefold amount in respect of the amount of the compound of the formula (III) on the weight basis and maintaining the mixture under stirring at room temperatures, ~:
usually 15-25C for 1-3 hours In the third aspect process of this invention, the step (2) is also applicable,.if desired, to the 3',4'-episulfide derivative of the formula (III) which has been isolated from the 3',4'-dideoxy-3'-eno derivative o:f the formula (II), but: it is usually advantageous to apply the step (2) directly to the reaction mixture from the step (l) containing both the compounds of the formulae (II) and (III) particularly in large scale operations.
We have further found that the 3 t, 4 9 -dideoxy-3'-eno derivatives of the formula (IV) can be produced from the 3',4'-epoxy derivatives of the formula (I) through another route involving four steps with a high overall yield. This route comprises the steps of (l) treating a 3',4'-epoxy derivative of the formula:
~765~i NHCOOR
0~ --~ ` ' .
NHCOOR
OCH2 O (I) Z\/~/
OH
wherein R and Z have the same meaning as de~ined above with an acylating~agent, for example benzoyl chloride, in a conventional manner to acylate the 2"-hydroxyl group, giving a compound of the formula:
, ~HCOOR
NaCOOR
`f \ ~ ~o. ~ OH
~ ~
NHCOOR
(V) ~ OCH2 O
Z\o 1~V
' ' OY
~76566 wherein R and Z have the same meaning as defined above and Y represents an acyl group;
(2) treating the compound of the formula (V) thus obtained with an alkali or alkaline earth metal iodide, for example sodium iodide, preferably in the presence of sodium acetate and glacial acetic acid, to give a compound of the formula:
:
.
~HCOOR ¦ NHCOOR
~ O ~ ~HCOOR
I ~ ~
NHCOOR
, OCH2 0 (VI) ~ Z\/o~
Y
~. .
where R, Z and Y have the same meaning as defined above;
: (3) subjecting the compound of the formula (VI) thus obtained to 3'-O~sulfonylation with a sulfonylating agent such as mesyl chloride, tosyl chloride and benzylsulfonyl chloride in a known manner, preferably in pyridine at a temperature below 10C, to form the compound of the formula:
: `
.` , .
- 18 - ~
, ' 7 Ei56~
CH2 l!lHCOOR
NHCOOR
I~ C~ ~
NHCOOR
OCH2 / (VII
Z~
OY
;: :
., where R, Z and Y have the same meaning as defined above and W represents mesyl, tosyl or benzylsulfonyl group, : (4:) heating the reaction mixture from the step (3) above~, ::
preferably to a temperature of 80 100C to convert the compound of the formula (VII) into the compound o~ the : ~ormula~
C~I2 ~HCOOR I NHCOOR
, . L~o ~
~ ~ o NHCOOR
'' ' /
.
( VIII ) \ o\ N~OGR/V
OY
~7~56~
wherein R, Z and Y nave the same meaning as defined above;
and (5) treating the compound of the formula (VIII) thus obtained with an alkali or alkaline earth metal alcoholate, for example sodium methoxide, in a known manner to give ~ 3',4'-dideoxy-3'-eno derivative of the formula (II) above.
; The compound, penta-amino~protected, 4",6"-hydroxyl-protected~ 3',4'-~-epoxy derivative of kanamycin B re-presented by the formula:
~ , .
., .
~ CH~2NHCOOR ¦ ~HCOOR
~_ 0 ~
~HCOOR
/ (IX) ' OCH2 0 ' ' Z/~O~ ' - ' \ o~HCOOR~
~ .
~ OH
, . .
, `~ 10 wherein R and Z have the same meaning as defined above which is to be used as starting compound of the first to third aspect processes according to this invention is a :
: new compound and constitutes another aspect of this invention.
-~. The new 3',4'-~-epoxy derivative of kanamycin B
of the formula (IX) can be derived from kanamycin B through several reaction steps as explained below. .
First of all, kanamycin B is subjected to amino-_ 20 s~
protecting step in a known manner. Thus, kanamycin B is reacted with a chloroformate of the formula RCOOCl wherein R represents a hydrogen atom or an alkyl or aryl group such as phenyl to protect all the five amino groups of kanamycin B in the form of urethane group -NHCOOR in the same manner as that described in Japanese Patent Publica-tion No.7595/75, affording penta N-protected kanamycin B
of the formula:
CE[2NHCOOR ~
~HCOOR
HCOOR
l~HCOOR
(X) HOCH2 ,O
: ~0~
~ HO\~
:
.
wherein R has the same meaning as defined above.
The next step is 4",6"-hydroxyl-protecting step which is also carried out in a known manner. Thus, the compound of the formula (X) may be reacted with a known hydroxyl-protecting agent selected from an a].kylidenating agent, an arylidenating agent, a cyclohexylidenating agent and a tetrahydropyranylidenating agent. Typical examples of such hydroxyl-protecting agent include acetaldehyde, 2',2'-dimethoxypropane, anisaldehyde, benzaldehyde, dimethyl-~765~
acetal, tolualdehyde, l,l-dimethoxycyclohexane and l,l-dimethoxytetrahydropyran. The reaction may preferably be carried out in a polar organic solvent, e.g. dimethyl-formamide in the presence of a catalytic amount of p-toluene sulfonic acid at room temperatures, for example 15~25C for 15~20 hours. This brings the selective in-troduction of the hydroxyl-protecting group in 4",6"-positions, thus yielding 4't,6"-O-protected derivative of the formula: -,' ' CH2~HCOOR
NHCOOR
~t ¦/ \t t/ \~HCOOR ,~
HO~ O~
NHCOOR
`~ (XI) Z~
' '' "
wherein R has the same meaning as defined above and Z
represents an alkylidene, arylidene, cyclohexylidene or tetrahydropyranylidene ~roup. In this selective reaction, it is desired that the temperature should be kept not to exceed 30C because there may also occur the attack of the hydroxyl~protecting agent on the 3'- and 4'-hydroxyl groups at higher temperatures.
~he compound of the formula (XI) is then subjected ~7~
to acylation reaction for the purpose of selective protec-tion of the 2"- and 3'-hydroxyl groups with hydroxyl-protecting group of an acyl type. The acylation step may usually be carried out by dissolving the compound of the formula (XI) in pyridine, adding an acylating agent such as an acyl chloride under a low temperature condition, preferably below 5C and maintain.ing the mixture under stirring for several hours.
Preferred acylating agent may be an acid chloride of an alkanoic acid having 2~4 carbon atoms such as acetyl chloride or an aroyl chloride such as benzoyl chloride.
The use of benzoyl chloride is most preferred. The use of a temperature below 5~C for the acylation step does not affect the 4~- and 5-hydroxyl groups which are relative-; ly low in reactivity. Thus, 2",31-diacyl derivative of the formula:
CH2~HCOOR~ NHCOOR
~0 1 .
NHCOOR
H~ ~ O \~
NHCOOR
/ (XII) Z~
OY
wherein R and Z have the same meaning as defined above, and X and Y each represent an acyl group, for example an alkanoyl, particularly a lower alkanoyl such as acetyl or an aroyl such as benzoyl may be produced.
In the acylation step, 2"-monoacylated derivative, i.e. a compound of the formula (XII), but wherein X re-presents a hydrogen atom may be obtained, if desired for some purposes, by conducting the acylation reaction under a milder conditions. Thus, in case of benzoyl chloride being used as acylating agent, a major proportion of 2t'-monobenzoyl derivative may be obtained under such condi-tions that benzoyl chloride is added at a temperature below 0C slowly and in small parts. On the other hand, at least a ma~or proportion of 2",3'-dibenzoyl derivative may be obtained when benzoyl chloride is added at a time at a temperature between 0C and room temperatures, pref-erably 0C and 5C. If 2"-monoacyl and 2",3'-diacyl deri~atives are obtained in the form of a mixture, the isolation of the respective derivatives may be effected by a chromatographic separation technique in a known manner, per se, for example by silica-gel thin-layer chromatography using 2:1 by volume of chloroform-methanol as developer.
The compound of the formula (XII) is then subjected to 4'-0-sulfonylation to form 4'-0-sulfonylated derivative of the formula:
' ~6S~
NHCOOR
UO~ ~Y I
N~COOR
(XIII ) O~H2 Z\/o ~
~
wherein R, Z, X and Y have the same meaning aB defined above and W represents mesyl, tosyl or benzylsulfonyl group. This step may preferably be carried out by re-acting the compound of the formu:la (XII) with~mesyl chlo-ride, tosyl chloride-or benzylsu:Lfonyl chlorlde in pyridine.
The 4'-0-sulfonylation may be~conducked at a temperature of up to 50C. The most pre~erred sulfonylating agent is mesyl chloride.
:
The 4'-0-sulfonylated derivative of the formula (XIII) thus obtained~is then converted to 31,4'-~-epoxy derivative of the formula (IX) above-mentioned as main product by treating it with a metal alcoholate. The epoxidation reaction may preferably be carried out by dissolving the compound of the formula (XIII) in a solvent, for example water, a lower alkanol such as methanol or ethanol, diglyme, sulforane, tetrahydrofuran or dimethyl-sulfoxide, adding to the solution a metal alcoholate, : : :
~ 25 _ :' ~ .
' '~ ' ' ' ' ':
: . :
- ~7~
usually an alkali or alkaline earth metal alcoholate such as sodium, potassium, or lithium alcoholate, particularly a lower alkoxide, for example sodium methoxide or sodium ethoxide and maintaining the mixture at room temperatures, usually 15~25C, suitably for 1~3 hours. During the epoxidation reaction, the hydroxyl-protecting group Y in the 2"-position is removed because of alkaline condition, thus the ~ree 2"-OH group is regenerated in the 3',4'-~-epoxidized derivative o~ the formula (IX).
3',4'-a-Epoxy derivative corresponding to the 3',
~ ~7~5~i6 .
C~I2N~I2 ~2 NIIZ
HOCH2 o ( IV ) '~ ,/~ 0 / :
¦~: N~32 ~V
HO \~/
` ~ : OH
.
.' .
and (4) hydrogenating the compound thus formed in a conventional manner to form 3',4'~dideoxykanamycin B;
and, if desired, converting the compound thus~formed into an acid additlon salt thereof.
The steps (1)~,(2) and (4) of the second~aspect process o~ this invention correspond to the steps (l), (2) and (4) of~the first aspect process as above-mentioned~?
respectively. ~ ~ -:
The step (3~ of the second aspect process~ i.e. the treatment of the 3',4'-eplsulfide der1vative of the formula :
(III) with an acid may preferably be carried out i~ a lower ~
. .
alkanol such as methanol and ethanol using a hydrohalogenic acid such as concentrated hydrochloric acid and hydrobromic acid. In general ? however ? a non-oxidizing mineral acid, for example sulfurlc acid, may be used for this treatment.
Preferably, the treatment may be carried out at a tempera-ture of 0~30C.
.' - 12 - ~
;
.:
.. . . . . .
. , . , , ' , . ' .
. . ' . '.
~7~
According to a third aspect process of this inven-tion, there is provided a process for the preparation of 3',4'-dideoxykanamycin B or its acid addition salts and int~E~a*es thereof ~x~rismg one or more of the foll~ng steps:
(1) treating with a xanthate a 3',4' epoxy derivative of an amino- and hydroxyl-protected kanamycin B of the formula:
;
CH2l~XCOOR ¦ NHCOOR
~0 ~NHCOOR
~ ~\~
~ICOOR
OC~I2 o (I) Z~
. , .
OH.
wherein R represents a hydrogen atom or an alkyl or aryl group and Z represents an alkylidene; arylidene, cyclo-hexylidene or tetrahydropyranylidene group whereby to form a 3'g4'-episulfido-kanamycin B.derivative of:the fo~mula:
~ 65~6 CB2~HCOOR I~HCOOR
Coo~ ~
NHCOOR
OCH2 ( III ) . .
Z/~ \l / :
HCOOR /V
` 'H' OH
. ~
wherein R and Z have the same meaning as defined above and 3 t, 4'-episulfide group is in a- or ~-position together : with a 3',4'-dideoxy-3'-eno-kanamycin ~ derivative of the formula: :
:: :
CH2NHCOOR j ~IHCOOR
o~
NHCOOR
( II ) z/l/~
OH
.
.. : .
~765i~
wherein R and Z have the same meaning as defined above;
(2) treating the reaction mixture from the step (1) with hydrazine or Raney nickel to convert the 3',4'-episulfide derivative of the formula (III) into a further amount of the 3',4'-dideoxy-3'-eno-kanamycin B derivative of the formula (II) above;
(3) removin~ the amino-protecting groups -COOR and hydroxyl-; protecting group Z of the 3',4'-dideoxy-3'-eno derivative thus formed in a conventional manner to form 3',4'-dideoxy-3'-eno-kanamycin B of the formula:
' ~u\
; / (IV~
HOCH2 o/
,'`,' ' '~ ~/
' ' HO ~
OH
' and (4) hydrogenating the compound thus formed in a con-ventional manner to form 3',4'-dideoxykanamycin B; and, if desired, converting the compound thus formed into an acid addition salt thereof.
The steps (1),(3) and (4) of the third aspect process of this invention correspond to the steps (1),(3) and (4) of the first aspect process as above-mentioned, respectively.
65~ii6 In the step (2) of the third aspect process, the treatment with hydrazine may preferably be effected in a lower alkanol such as methanol and ethanol using hydrazine, particularly in the form of hydrate NH2NH2-H20~ at room temperatures, usually 15~-25C. The amount of hydrazine to be used may preferably be about 10~30 moles per mole of the compound of the formula (III). The treatment with Raney nickel, if adopted for the step (2), may preferably .~
be carried out by dissolving the compound of the formula -(III) in a lower alkanol, for example methanol, adding Raney nickel to:the:solution in an appropriate amount, for .example threefold amount in respect of the amount of the compound of the formula (III) on the weight basis and maintaining the mixture under stirring at room temperatures, ~:
usually 15-25C for 1-3 hours In the third aspect process of this invention, the step (2) is also applicable,.if desired, to the 3',4'-episulfide derivative of the formula (III) which has been isolated from the 3',4'-dideoxy-3'-eno derivative o:f the formula (II), but: it is usually advantageous to apply the step (2) directly to the reaction mixture from the step (l) containing both the compounds of the formulae (II) and (III) particularly in large scale operations.
We have further found that the 3 t, 4 9 -dideoxy-3'-eno derivatives of the formula (IV) can be produced from the 3',4'-epoxy derivatives of the formula (I) through another route involving four steps with a high overall yield. This route comprises the steps of (l) treating a 3',4'-epoxy derivative of the formula:
~765~i NHCOOR
0~ --~ ` ' .
NHCOOR
OCH2 O (I) Z\/~/
OH
wherein R and Z have the same meaning as de~ined above with an acylating~agent, for example benzoyl chloride, in a conventional manner to acylate the 2"-hydroxyl group, giving a compound of the formula:
, ~HCOOR
NaCOOR
`f \ ~ ~o. ~ OH
~ ~
NHCOOR
(V) ~ OCH2 O
Z\o 1~V
' ' OY
~76566 wherein R and Z have the same meaning as defined above and Y represents an acyl group;
(2) treating the compound of the formula (V) thus obtained with an alkali or alkaline earth metal iodide, for example sodium iodide, preferably in the presence of sodium acetate and glacial acetic acid, to give a compound of the formula:
:
.
~HCOOR ¦ NHCOOR
~ O ~ ~HCOOR
I ~ ~
NHCOOR
, OCH2 0 (VI) ~ Z\/o~
Y
~. .
where R, Z and Y have the same meaning as defined above;
: (3) subjecting the compound of the formula (VI) thus obtained to 3'-O~sulfonylation with a sulfonylating agent such as mesyl chloride, tosyl chloride and benzylsulfonyl chloride in a known manner, preferably in pyridine at a temperature below 10C, to form the compound of the formula:
: `
.` , .
- 18 - ~
, ' 7 Ei56~
CH2 l!lHCOOR
NHCOOR
I~ C~ ~
NHCOOR
OCH2 / (VII
Z~
OY
;: :
., where R, Z and Y have the same meaning as defined above and W represents mesyl, tosyl or benzylsulfonyl group, : (4:) heating the reaction mixture from the step (3) above~, ::
preferably to a temperature of 80 100C to convert the compound of the formula (VII) into the compound o~ the : ~ormula~
C~I2 ~HCOOR I NHCOOR
, . L~o ~
~ ~ o NHCOOR
'' ' /
.
( VIII ) \ o\ N~OGR/V
OY
~7~56~
wherein R, Z and Y nave the same meaning as defined above;
and (5) treating the compound of the formula (VIII) thus obtained with an alkali or alkaline earth metal alcoholate, for example sodium methoxide, in a known manner to give ~ 3',4'-dideoxy-3'-eno derivative of the formula (II) above.
; The compound, penta-amino~protected, 4",6"-hydroxyl-protected~ 3',4'-~-epoxy derivative of kanamycin B re-presented by the formula:
~ , .
., .
~ CH~2NHCOOR ¦ ~HCOOR
~_ 0 ~
~HCOOR
/ (IX) ' OCH2 0 ' ' Z/~O~ ' - ' \ o~HCOOR~
~ .
~ OH
, . .
, `~ 10 wherein R and Z have the same meaning as defined above which is to be used as starting compound of the first to third aspect processes according to this invention is a :
: new compound and constitutes another aspect of this invention.
-~. The new 3',4'-~-epoxy derivative of kanamycin B
of the formula (IX) can be derived from kanamycin B through several reaction steps as explained below. .
First of all, kanamycin B is subjected to amino-_ 20 s~
protecting step in a known manner. Thus, kanamycin B is reacted with a chloroformate of the formula RCOOCl wherein R represents a hydrogen atom or an alkyl or aryl group such as phenyl to protect all the five amino groups of kanamycin B in the form of urethane group -NHCOOR in the same manner as that described in Japanese Patent Publica-tion No.7595/75, affording penta N-protected kanamycin B
of the formula:
CE[2NHCOOR ~
~HCOOR
HCOOR
l~HCOOR
(X) HOCH2 ,O
: ~0~
~ HO\~
:
.
wherein R has the same meaning as defined above.
The next step is 4",6"-hydroxyl-protecting step which is also carried out in a known manner. Thus, the compound of the formula (X) may be reacted with a known hydroxyl-protecting agent selected from an a].kylidenating agent, an arylidenating agent, a cyclohexylidenating agent and a tetrahydropyranylidenating agent. Typical examples of such hydroxyl-protecting agent include acetaldehyde, 2',2'-dimethoxypropane, anisaldehyde, benzaldehyde, dimethyl-~765~
acetal, tolualdehyde, l,l-dimethoxycyclohexane and l,l-dimethoxytetrahydropyran. The reaction may preferably be carried out in a polar organic solvent, e.g. dimethyl-formamide in the presence of a catalytic amount of p-toluene sulfonic acid at room temperatures, for example 15~25C for 15~20 hours. This brings the selective in-troduction of the hydroxyl-protecting group in 4",6"-positions, thus yielding 4't,6"-O-protected derivative of the formula: -,' ' CH2~HCOOR
NHCOOR
~t ¦/ \t t/ \~HCOOR ,~
HO~ O~
NHCOOR
`~ (XI) Z~
' '' "
wherein R has the same meaning as defined above and Z
represents an alkylidene, arylidene, cyclohexylidene or tetrahydropyranylidene ~roup. In this selective reaction, it is desired that the temperature should be kept not to exceed 30C because there may also occur the attack of the hydroxyl~protecting agent on the 3'- and 4'-hydroxyl groups at higher temperatures.
~he compound of the formula (XI) is then subjected ~7~
to acylation reaction for the purpose of selective protec-tion of the 2"- and 3'-hydroxyl groups with hydroxyl-protecting group of an acyl type. The acylation step may usually be carried out by dissolving the compound of the formula (XI) in pyridine, adding an acylating agent such as an acyl chloride under a low temperature condition, preferably below 5C and maintain.ing the mixture under stirring for several hours.
Preferred acylating agent may be an acid chloride of an alkanoic acid having 2~4 carbon atoms such as acetyl chloride or an aroyl chloride such as benzoyl chloride.
The use of benzoyl chloride is most preferred. The use of a temperature below 5~C for the acylation step does not affect the 4~- and 5-hydroxyl groups which are relative-; ly low in reactivity. Thus, 2",31-diacyl derivative of the formula:
CH2~HCOOR~ NHCOOR
~0 1 .
NHCOOR
H~ ~ O \~
NHCOOR
/ (XII) Z~
OY
wherein R and Z have the same meaning as defined above, and X and Y each represent an acyl group, for example an alkanoyl, particularly a lower alkanoyl such as acetyl or an aroyl such as benzoyl may be produced.
In the acylation step, 2"-monoacylated derivative, i.e. a compound of the formula (XII), but wherein X re-presents a hydrogen atom may be obtained, if desired for some purposes, by conducting the acylation reaction under a milder conditions. Thus, in case of benzoyl chloride being used as acylating agent, a major proportion of 2t'-monobenzoyl derivative may be obtained under such condi-tions that benzoyl chloride is added at a temperature below 0C slowly and in small parts. On the other hand, at least a ma~or proportion of 2",3'-dibenzoyl derivative may be obtained when benzoyl chloride is added at a time at a temperature between 0C and room temperatures, pref-erably 0C and 5C. If 2"-monoacyl and 2",3'-diacyl deri~atives are obtained in the form of a mixture, the isolation of the respective derivatives may be effected by a chromatographic separation technique in a known manner, per se, for example by silica-gel thin-layer chromatography using 2:1 by volume of chloroform-methanol as developer.
The compound of the formula (XII) is then subjected to 4'-0-sulfonylation to form 4'-0-sulfonylated derivative of the formula:
' ~6S~
NHCOOR
UO~ ~Y I
N~COOR
(XIII ) O~H2 Z\/o ~
~
wherein R, Z, X and Y have the same meaning aB defined above and W represents mesyl, tosyl or benzylsulfonyl group. This step may preferably be carried out by re-acting the compound of the formu:la (XII) with~mesyl chlo-ride, tosyl chloride-or benzylsu:Lfonyl chlorlde in pyridine.
The 4'-0-sulfonylation may be~conducked at a temperature of up to 50C. The most pre~erred sulfonylating agent is mesyl chloride.
:
The 4'-0-sulfonylated derivative of the formula (XIII) thus obtained~is then converted to 31,4'-~-epoxy derivative of the formula (IX) above-mentioned as main product by treating it with a metal alcoholate. The epoxidation reaction may preferably be carried out by dissolving the compound of the formula (XIII) in a solvent, for example water, a lower alkanol such as methanol or ethanol, diglyme, sulforane, tetrahydrofuran or dimethyl-sulfoxide, adding to the solution a metal alcoholate, : : :
~ 25 _ :' ~ .
' '~ ' ' ' ' ':
: . :
- ~7~
usually an alkali or alkaline earth metal alcoholate such as sodium, potassium, or lithium alcoholate, particularly a lower alkoxide, for example sodium methoxide or sodium ethoxide and maintaining the mixture at room temperatures, usually 15~25C, suitably for 1~3 hours. During the epoxidation reaction, the hydroxyl-protecting group Y in the 2"-position is removed because of alkaline condition, thus the ~ree 2"-OH group is regenerated in the 3',4'-~-epoxidized derivative o~ the formula (IX).
3',4'-a-Epoxy derivative corresponding to the 3',
4'-~-epoxy derivative of the formula (IX) may be derived from 3t-O-tosyl derlvative corresponding to the 4'~O-sulfonylated derivative of the formula (XIII) above, i.e.
the compound of the formula (XIII), but whereln W is hydrogen and X is tosyl group in the same manner as that of the 3',4'-epoxidation step as above-mentioned, i.e.
by treating with an alkali-metal alcoholate such as sodium methoxide, details~of which is given in DT OS No.2,555,479.
A diagramatic reaction scheme is given below to ;~ 20 show the preparation of 3',4'-dideoxykanamycin B starting from kanamyoln B via a new intermediate, 3',4'-~-epoxy derivative of the formula (IX), which is treated according to the processes :f this lnvention.
:
.
. ' ~
~76~,6~
Kanamycin B
¦ Protection of five NH2 groups ~ with -COOR group COO:~
~HCOOR
' . / :
.-~ O
:0c~2 'I
COOR
HO
¦ Protection of 4"- and 6 OH groups with group Z
CX2NHCOOR ¦NHCOOR
, ~ 0 ~ ~ ~HCOOR
~/~
~ NHCOOR
: O ':' , /,~0' \ ~ NHCOOR ~ ~
- 'H ' OH
, :
- ~
.
the compound of the formula (XIII), but whereln W is hydrogen and X is tosyl group in the same manner as that of the 3',4'-epoxidation step as above-mentioned, i.e.
by treating with an alkali-metal alcoholate such as sodium methoxide, details~of which is given in DT OS No.2,555,479.
A diagramatic reaction scheme is given below to ;~ 20 show the preparation of 3',4'-dideoxykanamycin B starting from kanamyoln B via a new intermediate, 3',4'-~-epoxy derivative of the formula (IX), which is treated according to the processes :f this lnvention.
:
.
. ' ~
~76~,6~
Kanamycin B
¦ Protection of five NH2 groups ~ with -COOR group COO:~
~HCOOR
' . / :
.-~ O
:0c~2 'I
COOR
HO
¦ Protection of 4"- and 6 OH groups with group Z
CX2NHCOOR ¦NHCOOR
, ~ 0 ~ ~ ~HCOOR
~/~
~ NHCOOR
: O ':' , /,~0' \ ~ NHCOOR ~ ~
- 'H ' OH
, :
- ~
.
5~
Protection of 2"- and 3'-OH groups with acyl groups . ~ Y and X, respectively ; CH2NHCOOR ~HCOOR
. ~0 ~ '~.''` ' NHCOOR
HO
o o ~: Z\~/ ' ~'.' ¦ 4'-O-Sulfonylation ~ l (Introduction of:W group) : CH2NHCOOR NHCOOR
~ ~ ~ COOR ~ ~ -. WO~ O--~
, / .,1--HCOOR
' ~ \~/ ' oy . 3',4'-Epoxidation with .~, , , i ~ an: alcoholate , CH2~XCOOR ~IHCOOR
o ,~ :
HCOOR
," ~--\f~/~ '. :, 1~ NHCOOR
~ C~2 / ~O O
' .
' ~ 71~6~
Treatment with a xanthate (Route A)(Route B)(Route C) 1- ._ ~CF~HCOOR ~,R ~HCOOR ~HCOOR
ICOOR / ~ HCOOR
~ ~ ~ (~-0~
NHCOOR / ~COOR
OCHz OCH2 Z/ ~/ Z~
OH
Treatment with . hydrazine or Raney nickel (Route C) ~ .
Treatment Hydrogenation Removal of the NH2-and OH-protections with an acid (Route D) (Route A)(Route C) 1 (Route B) ,~ ~ ~ 1, , CH2NHCOOR ~COOR ~2~H2 I~H2 ~_ o ~COO~ 6~ o ~ ~ ;
/
O O
Z~o~! ~~' . OH OH
:
_ ~9 -- ~
~L~3)76566 \ Removal of the \ NH 2- and OH-protections /Hydrogenation \(Route D) ¦ (RouteA)(Route B)(Route C) ; ' ~U `l ,, CH2~2 NH2 ~ ~ ~
. l!lH2 `
. ~ /
O
. ~ O
` ~NH
~ \I V
OH
Route A = The first aspect process of this invention Route B = The second aspect process of this invention Route C = The third aspect process of this invention:
Route D = An alternative of the first or third aspect process of tbis iLven~ion '` ~
.
. .
.' '' ' `- ~. ' .:
PREFERRED EMBODIMENTS OF THE INVENTION:
This invention is further illustrated by way of Examples which include overall steps starting from kanamycin B and leading to the final product, 3'g4'-dideoxykanamycin B, through several routes according to khis invention.
Example 1 (1) Preparation of penta-N-ethoxycarbonylkanamycin B
Penta-N-ethoxycarbonylkanamycin B was prepared from kanamycin B free base by the method described in Example 1 of British Patent No.1,349,302.
(2) Preparation of 2",3'-di-0-benzoyl-penta-N-ethoxycarbonyl-4",6"-0-cyclohexylidene-kanamycin B
Penta-N-ethoxycarbonylkanamycin B (10 g) was suspended in dimethylformamide (70~1 ), to which was added p-toluene sulfonic acid until the pH of ~ `
: the suspension was lowered below 3.0 and then added cyclohexanedimethylketal (10 ml). The mixture was maintained at 25C under stirring for 18 hours. The completion o~ the reaction was con~irmed by thin layer .
chromatography using silica gel (made by Merck) as ~:
stationary phase and chloroform-methanol (10:1 by volume) as developer and the resulting reaction mix~
ture was neutralized with triethylamine. The neu~
tralized liquid was concentrated under vacuum to obtain a residual liquid of 25 ml which was then dis-solved in pyridine (150 ml). After cooling the solution to a temperature of 0~5C, benzoyl chloride (3.9 ml) was added thereto and the mixture was kept to cause reaction for 3 hours. The completion of reaction ~t~7~5t~
was confirmed by thln layer chromatography. Water (5 ml~ was added to the resulting mixture and the mixture was stirred at room temperature for 30 minutes, concentrated and poured into wa~er (200 ml) to form preclpitate which was recovered by ~iltration.
Yield 12.7 g (95%). After the purification by a conventional siiica-gel chromatography, the titled compound had the following physical properties:
~]D ~ 76.6 (c=17~ pyridine); mp. 233~235C.
Elementary analysis:
Found: C 55.98; H 6.44; N 5.60%
Calculated for Cs3H73Ns22:
C 56.22; H 6.51; N 6.19%
(3) Preparation of 2",3'-di-O-benzoyl-penta-N-; ethoxycarbonyl-4",6"-0-cyclohexylidene-4'-O-mesyl-kanamycin B
2",3'-dl-O-benzoyl-penta-N-ethoxycarbonyl-4",
Protection of 2"- and 3'-OH groups with acyl groups . ~ Y and X, respectively ; CH2NHCOOR ~HCOOR
. ~0 ~ '~.''` ' NHCOOR
HO
o o ~: Z\~/ ' ~'.' ¦ 4'-O-Sulfonylation ~ l (Introduction of:W group) : CH2NHCOOR NHCOOR
~ ~ ~ COOR ~ ~ -. WO~ O--~
, / .,1--HCOOR
' ~ \~/ ' oy . 3',4'-Epoxidation with .~, , , i ~ an: alcoholate , CH2~XCOOR ~IHCOOR
o ,~ :
HCOOR
," ~--\f~/~ '. :, 1~ NHCOOR
~ C~2 / ~O O
' .
' ~ 71~6~
Treatment with a xanthate (Route A)(Route B)(Route C) 1- ._ ~CF~HCOOR ~,R ~HCOOR ~HCOOR
ICOOR / ~ HCOOR
~ ~ ~ (~-0~
NHCOOR / ~COOR
OCHz OCH2 Z/ ~/ Z~
OH
Treatment with . hydrazine or Raney nickel (Route C) ~ .
Treatment Hydrogenation Removal of the NH2-and OH-protections with an acid (Route D) (Route A)(Route C) 1 (Route B) ,~ ~ ~ 1, , CH2NHCOOR ~COOR ~2~H2 I~H2 ~_ o ~COO~ 6~ o ~ ~ ;
/
O O
Z~o~! ~~' . OH OH
:
_ ~9 -- ~
~L~3)76566 \ Removal of the \ NH 2- and OH-protections /Hydrogenation \(Route D) ¦ (RouteA)(Route B)(Route C) ; ' ~U `l ,, CH2~2 NH2 ~ ~ ~
. l!lH2 `
. ~ /
O
. ~ O
` ~NH
~ \I V
OH
Route A = The first aspect process of this invention Route B = The second aspect process of this invention Route C = The third aspect process of this invention:
Route D = An alternative of the first or third aspect process of tbis iLven~ion '` ~
.
. .
.' '' ' `- ~. ' .:
PREFERRED EMBODIMENTS OF THE INVENTION:
This invention is further illustrated by way of Examples which include overall steps starting from kanamycin B and leading to the final product, 3'g4'-dideoxykanamycin B, through several routes according to khis invention.
Example 1 (1) Preparation of penta-N-ethoxycarbonylkanamycin B
Penta-N-ethoxycarbonylkanamycin B was prepared from kanamycin B free base by the method described in Example 1 of British Patent No.1,349,302.
(2) Preparation of 2",3'-di-0-benzoyl-penta-N-ethoxycarbonyl-4",6"-0-cyclohexylidene-kanamycin B
Penta-N-ethoxycarbonylkanamycin B (10 g) was suspended in dimethylformamide (70~1 ), to which was added p-toluene sulfonic acid until the pH of ~ `
: the suspension was lowered below 3.0 and then added cyclohexanedimethylketal (10 ml). The mixture was maintained at 25C under stirring for 18 hours. The completion o~ the reaction was con~irmed by thin layer .
chromatography using silica gel (made by Merck) as ~:
stationary phase and chloroform-methanol (10:1 by volume) as developer and the resulting reaction mix~
ture was neutralized with triethylamine. The neu~
tralized liquid was concentrated under vacuum to obtain a residual liquid of 25 ml which was then dis-solved in pyridine (150 ml). After cooling the solution to a temperature of 0~5C, benzoyl chloride (3.9 ml) was added thereto and the mixture was kept to cause reaction for 3 hours. The completion of reaction ~t~7~5t~
was confirmed by thln layer chromatography. Water (5 ml~ was added to the resulting mixture and the mixture was stirred at room temperature for 30 minutes, concentrated and poured into wa~er (200 ml) to form preclpitate which was recovered by ~iltration.
Yield 12.7 g (95%). After the purification by a conventional siiica-gel chromatography, the titled compound had the following physical properties:
~]D ~ 76.6 (c=17~ pyridine); mp. 233~235C.
Elementary analysis:
Found: C 55.98; H 6.44; N 5.60%
Calculated for Cs3H73Ns22:
C 56.22; H 6.51; N 6.19%
(3) Preparation of 2",3'-di-O-benzoyl-penta-N-; ethoxycarbonyl-4",6"-0-cyclohexylidene-4'-O-mesyl-kanamycin B
2",3'-dl-O-benzoyl-penta-N-ethoxycarbonyl-4",
6"-0-cyclohexylidene-kanamycin B (5g) was dissolved in pyridine (100 ml3, to which was added mesyl chloride (1.4 ml) and the mixture was maintained at 40C under :
~stirring ~or 1.5 hours. After the mix~ure was cooled to room temperature, water (5~ml) was added to the mixture to decompose~the excess mesyl chloride and the mixture was concentrated. To the concentrate was .
added water (200 ml) to precipitate the titled compound, which was recovered by filtration. Yield 5.0g t94%);
~a]~ 103.6 (c=l.0, pyridine); mp. 176~179C.
Elementary analysis:
Found: C 53.28; H 6.25; N 5.41; S 2.95%
~ 30 Calculated for Cs 4 H 75 Ns 24S:
:' ~76~66 C 53.59; H 6.25; N 5.79, S 2.65%
(4) Preparation of 3',4'-~-epoxy-penta-N-ethoxy-carbonyl-4",6"-0-cyclohexylidene-kanamycin B
2"~,3'-Di-0-benzoyl-penta-N-ethoxycarbonyl-4",6"-0-cyclohexylidene~4'-mesyl-kanamycin B (5 g) was dissolved in methanol (100 ml), to which was added sodium methylate (2.2 g). The mixture was maintained at room temperature under stirring for 2 hours. After the completion of reaction was con-f~rmed by thin layer chromatography using silica gel as stationary phase and carbon tetrachloride-aceto~e tl:l by volume) as developer, the reaction mixture was ice-cooled, neutralized with concentrated hydro-chloric acid (1.25 mlj and concentrated. To the neutralized concentrate was added water (100 ml) to precipitate the titled compound which was recovered by filtration. Yield 3.5 g (95%); ~]D + 37.8 (c=l.0, pyridine), mp. 254~258C (decomposition with foaming).
Elementary analysis:
.
;~ 20 Found: C 51.86; H 6.89; N 7.58; 0 33.67%
- Calculated for C 3 g H~3NsOls:
.
C 51.69, H 7.02; N 7.73; 0 33.55%
(5) Preparation of 3',4'-dideoxy-3'-eno-penta-N-etboxycarbonyl~4"~,6"-0-cyclohexylidene-kanamyGin B
3',4'-~-Epoxy~penta-N-ethoxycarbonyl-4",6"-0-cyclohexylidene-kanamycin B (80o mg) was suspended in n-butanol (40 ml), to which was then added potassium n-butylxanthate (1.7 g) and the reaction was conducted at 80C for 4 hours. After the completion of reaction was confirmed by silica-gel thin layer chromatography .
~ - 33 ~L~7~
using carbon tetrachloride-acetone (1:1 by volume) as developer, the mixture was cooled and washed with water (4G ml x 2) and the resulting butanol layer was concentrated to dryness. Yield 900 mg. This was confirmed by silica-gel thin layer chromatography to be a mixture of 3',4l-dideoxy-3'-eno-penta-N~ethoxy-- carbonyl-4 1l, 6"-cyclohexylidene-kanamycin B and 3l,4t_ ; episulfido-penta-N-ethoxycarbonyl-4",6"-O-cyclohexyli-dene-kanamycin B in approximately 1:1 proportion.
The mixture was subjected to silica-gel thin layer chromatography using carbon tetrachloride-acetone ; (5:1 by volume) as developer, affording 3',4'-dideoxy-3'-eno-penta-N-ethoxycarbonyl-4",6"-cyclohexylidene-kanamycin B with [a32D f + 24.7 (c=l.0, methanol) and 3',4'-episulfido-penta-N-ethoxycarbonyi-4",6"-O-cyclo-2s hexylidene-kanamycin B with []D of ~ 10.8 (c~=l.0, H20j and melting point of 250-260C (with decomposi-tion), separately.
Elementary analysis of the latter compound:
Found: C 50.41; H 6~.95, N~7.45; S 3.48%
Calculated for C39H63NsO~sS:
~ C 50.79; H 6.90; N 7.60; S 3.48%
(6) Preparation of 3l,4l-dideoxy-3'-eno-kanamycin B
3'~4'-Dideoxy-3l-eno-penta-N-ethoxycarbonyl-4l',6"-0-cyclohexylidene kanamycin B (475 mg) was dissolved in methanol (5 ml), to which was added an amount of 1 N HCl sufficient to adjust the pH value of the solution to 2Ø The solution was heated at 50C for 30 minutes and, after adding water (5 ml) and then barium hydroxide octahydrate (1.4 g)~ further ~L~765~6 heated to distill off the methanol and the remaining mixture was refluxed for 8 hours and then cooled.
Carbon dioxide gas was passed through the cooled mixture and barium carbonate thus formed was removed by filtration. Purification through a column of Amberlite CG-50 (NH4 form) gave the titled com-pound. Yield 560 mg (26%).
Elementary analysis:
Found: C 47.85, H 7.~5; N 15.40%
Calculated for C18H35Ns08:
C 48.11; H 7.80; N 15.59%
~stirring ~or 1.5 hours. After the mix~ure was cooled to room temperature, water (5~ml) was added to the mixture to decompose~the excess mesyl chloride and the mixture was concentrated. To the concentrate was .
added water (200 ml) to precipitate the titled compound, which was recovered by filtration. Yield 5.0g t94%);
~a]~ 103.6 (c=l.0, pyridine); mp. 176~179C.
Elementary analysis:
Found: C 53.28; H 6.25; N 5.41; S 2.95%
~ 30 Calculated for Cs 4 H 75 Ns 24S:
:' ~76~66 C 53.59; H 6.25; N 5.79, S 2.65%
(4) Preparation of 3',4'-~-epoxy-penta-N-ethoxy-carbonyl-4",6"-0-cyclohexylidene-kanamycin B
2"~,3'-Di-0-benzoyl-penta-N-ethoxycarbonyl-4",6"-0-cyclohexylidene~4'-mesyl-kanamycin B (5 g) was dissolved in methanol (100 ml), to which was added sodium methylate (2.2 g). The mixture was maintained at room temperature under stirring for 2 hours. After the completion of reaction was con-f~rmed by thin layer chromatography using silica gel as stationary phase and carbon tetrachloride-aceto~e tl:l by volume) as developer, the reaction mixture was ice-cooled, neutralized with concentrated hydro-chloric acid (1.25 mlj and concentrated. To the neutralized concentrate was added water (100 ml) to precipitate the titled compound which was recovered by filtration. Yield 3.5 g (95%); ~]D + 37.8 (c=l.0, pyridine), mp. 254~258C (decomposition with foaming).
Elementary analysis:
.
;~ 20 Found: C 51.86; H 6.89; N 7.58; 0 33.67%
- Calculated for C 3 g H~3NsOls:
.
C 51.69, H 7.02; N 7.73; 0 33.55%
(5) Preparation of 3',4'-dideoxy-3'-eno-penta-N-etboxycarbonyl~4"~,6"-0-cyclohexylidene-kanamyGin B
3',4'-~-Epoxy~penta-N-ethoxycarbonyl-4",6"-0-cyclohexylidene-kanamycin B (80o mg) was suspended in n-butanol (40 ml), to which was then added potassium n-butylxanthate (1.7 g) and the reaction was conducted at 80C for 4 hours. After the completion of reaction was confirmed by silica-gel thin layer chromatography .
~ - 33 ~L~7~
using carbon tetrachloride-acetone (1:1 by volume) as developer, the mixture was cooled and washed with water (4G ml x 2) and the resulting butanol layer was concentrated to dryness. Yield 900 mg. This was confirmed by silica-gel thin layer chromatography to be a mixture of 3',4l-dideoxy-3'-eno-penta-N~ethoxy-- carbonyl-4 1l, 6"-cyclohexylidene-kanamycin B and 3l,4t_ ; episulfido-penta-N-ethoxycarbonyl-4",6"-O-cyclohexyli-dene-kanamycin B in approximately 1:1 proportion.
The mixture was subjected to silica-gel thin layer chromatography using carbon tetrachloride-acetone ; (5:1 by volume) as developer, affording 3',4'-dideoxy-3'-eno-penta-N-ethoxycarbonyl-4",6"-cyclohexylidene-kanamycin B with [a32D f + 24.7 (c=l.0, methanol) and 3',4'-episulfido-penta-N-ethoxycarbonyi-4",6"-O-cyclo-2s hexylidene-kanamycin B with []D of ~ 10.8 (c~=l.0, H20j and melting point of 250-260C (with decomposi-tion), separately.
Elementary analysis of the latter compound:
Found: C 50.41; H 6~.95, N~7.45; S 3.48%
Calculated for C39H63NsO~sS:
~ C 50.79; H 6.90; N 7.60; S 3.48%
(6) Preparation of 3l,4l-dideoxy-3'-eno-kanamycin B
3'~4'-Dideoxy-3l-eno-penta-N-ethoxycarbonyl-4l',6"-0-cyclohexylidene kanamycin B (475 mg) was dissolved in methanol (5 ml), to which was added an amount of 1 N HCl sufficient to adjust the pH value of the solution to 2Ø The solution was heated at 50C for 30 minutes and, after adding water (5 ml) and then barium hydroxide octahydrate (1.4 g)~ further ~L~765~6 heated to distill off the methanol and the remaining mixture was refluxed for 8 hours and then cooled.
Carbon dioxide gas was passed through the cooled mixture and barium carbonate thus formed was removed by filtration. Purification through a column of Amberlite CG-50 (NH4 form) gave the titled com-pound. Yield 560 mg (26%).
Elementary analysis:
Found: C 47.85, H 7.~5; N 15.40%
Calculated for C18H35Ns08:
C 48.11; H 7.80; N 15.59%
(7) Preparation of 3',41-dideoxykanamycin B
3'4'-Dideoxy-3'-eno-kanamycin B (120 mg) was dissolved in water (4 ml), to which Raney nickel (0.2 ml) was added. Hydrogen was passed through the solution `
for 2 hours under atmospheric conditions of temperature ., . :
and pressure. After the catalys~ used was filte~red off, the ~iltrate was concentrated to dryness. Yield 108 mg `
(95%).
, ;~ 20 Example 2 (l~ Preparation of penta-N-t-butoxycarbonyl-kanamycin B
- Xanamycin B~(lO g) was added to a mixture of water (34 ml), triethylamine (24 ml) and dimethyl-Pormamide (48 ml). Then~ t-butyl-S-(4,6-dimethyl- ~
pyrimidin-2-yl)-thiol-carbonate (40 g) was added to the mixture at room temperature and the mixture was stirred at that temperature for 18 hours. Addition of water - (150 ml) to the mixture formed crystals which were re-covered by filtration and washed thoroughly with an aqueous saturated solution of ethyl acetate. Yield 20 . . .
~7~ii5~qE~ :
g (l00~). mp.229~~34C (decomposition with foaming).
Elementary analysis:
Found: C 52.61; H 7.86; N 6.93%
Calculated for C43H77NsO20:
C 52~47; H 7.90; N 7.12%
(2) Preparation of 3 t ~ 41-~-epoxy-penta-N~t-butoxy-carbonyl-4",6"-O-cyclohexylidene-kanamycin B
Penta-N-t-butoxykanamycln B (10 g) was treated in the same ways as those described in Example 1 (2), (3) and (4) above, yielding the titled compound. Yield 80%, ~a~2D ~ 27(c=l.O, pyrldine). mp. 232_234C
(decomposition with foaming).
(3) Preparation of 3',4'-episulfido-penta-N-t-butoxy-carbonyl-4",6"-O-cyclohexylidene-kanamycin B
3l~4'-~-Epoxy-penta-N-t-butoxyc~*x~yl-4~6~ ~ cyclo-hexylidene-kanamycin B (10 g) was suspended in n butanol 'l00 ml), to which was added potassium n-butylxanthate ~-(9 5 g) and the reaction was conducted at 90C for 2 hours. After the reaction was completed, the mixture was cooled and washed twice with l00 ml portions of water and the butanol layer separated was concentrated to dryness, affording a mixture comprising 3',4'-episulfido-penta-N-t-butoxycarbonyl-4",6~t-cyclohexylidene-kanamycin B and 3',4'-dideoxy-31-eno-penta-N-t-butoxy-carbonyl-4',6"-cyclohexylidene kanamycin B. Yield ll g.
The crude product was subjected to silica gel chromato-graphy using chloroform-methanol (50:l by volume) as developer, to isolate 31,4'-episulfido-penta-N-t-butoxy-carbonyl-4",6"-cyclohexylidene-kanamycin B. Yield 3.9 g (35%)- [~] D + 23 (c= l.0, pyridine). mp. 235~238C
(decomposition with foaming).
Elementary analysis:
Found: C 55.10; H 7.94; N 6.31; S 3.30%
Calculated for C~gH33NsOI8S:
C 55.39; H 7.89; N 6.59; S 3.02%
(4) Preparation of 3',4'-dideoxy-3'-eno-kanamycin B
3',4'-Episulfido-penta-N-t-butoxycarbonyl-4", 6"-0-cyclohexylidene-kanamycin B (1.15 g) was dissolved in methanol (12 ml)g to which was added concentrated ... .
10 hydrochloric acid (3 ml) and the reaction was conducted at room temperature for 3 hours.
The reaction mixture was concentrated to dryness and the resulting residue was dissolved in water (18 ml) and the pH of the solution was a~usted to 6.5 by the addition of lN sodium hydroxide solution (2.5 ml3.
The solution was passed through a column of 20 ml of Amberlite CG-50 (N~4+ form). The adsorbed column was washed with water and then O.lN aqueous ammonia and subsequently eluated with 0.3N aqueous ammonia. The concentration of the eluate gave the titled compound.
Yield 194 mg.
(5) Preparation o~f 3',4'-di~eoxykanamycin B
, .. . .
3'4'-Dideoxy-3'-eno-kanamycin B (120 mg) was dissolved in water (4~ml), to which was added Raney nickel (0.2 ml3 and hydrogen was passed through the mixture for 2 hours under atmospheric temperatùre and pressure ~conditions. After the catalyst was filtered off, the filtrate was concentrated to dryness, giving the tilted compound. Yield 108 mg (90%).
; 30 Example 3 * Trade ~Iark 7~ 6 Preparation of 3',4'-episulfido-penta-N-ethoxycarbonyl-4",6"-O-cyclohexylidene-kanamycin B
3',4'-~-Epoxy-penta-N-ethoxycarbonyl-4", 6 ~-o-~ cyclohexylidene-kanamycin B (100 mg) which was prepared : by the method described in Example l of DT-OS 2,555,479 was dissolved in pyridine (5 ml), to which was added potassium ethyl xanthate (100 mg) and the mixture was refluxed for l.5 hours and then concentrated to dryness.
A mixture of water and chloroform (2:3 by volume) was added to the solld residue and the chloroform layer was separated, was~hed three times with 20 ml portions of water and concentrated to dryness, yielding 70~mg of a crude product comprising 3',4'-episulfido-penta-N-ethoxycarbonyl-4",6"-O-cyclohexylidene-kanamycin B
and 3',4'-dideoxy-3'-eno-penta-N-ethoxycarbonyl-4",6"-O-cyclohexylidene~-kanamycin B.
The isolation of the respective compounds was carried out by thin layer chromatography ln the same manner as that used in Example 1 (5) above.
; 20 Example 4 ! (l) Preparation of 3',4l-dideoxy-3'-eno-penta-N-~ ~ !
ethoxycarbonyl-4",6"-O-cyclohexylidene~-kanamycin B
3',4'-Episulfido-penta-N-ethoxycarbonyl-4" ,6~-o-cyclohexylidene-kanamycin B (470 mg) which was prepared as described in Example l (5)(or Example 3tl)) above was dissolved in methanol (2 ml), to which was added hydrazine hydrate (0.22 ml) and the mixture was allowed to stand at room temperature for 2 hours. The reaction mixture was then concentrated to dryness and treated with water (20 ml) to form preclpitate which was re-` - 38 covered by filtration. Yield 362 mg (80%). [~]D
24.7 (c=l.0, methanol).
Elementary analysis:
Found: C 52.31; H 7.53; N 7.49%
Calculated for C3sH6 sNsOI a:
C 52.50; H 7.36; N 7.85%
(2) Preparation of 3',4'-dideoxy-3'-eno-kanamycin B
3',4~-Dideoxy-3 r -eno-penta-N-Ethoxycarbonyl-4'i, 6"-cyclohexylidene-kanamycin B (475 mg) was dissolved in methanol (5 ml) and treated in the same manner as that described in Example 1 (6), affordlng the titled compound.
; (3) Prepara~ion of 3',4'-dideoxykanamycin B
3',4'-Dideoxy-3i-eno-kanamycin B was treated as similar as in Example 1 (7), affording the titled compound.
Example 5 (1) Preparation of 3',4'-dideoxy-3'~-eno-penta-N-t-butoxy-4",6"-0-cyclohexylidene-kanamycin B
3',4'-Episul~ido-penta-N-t-butoxycarbonyl-4",6"-0-cyclohexylidene-kanamycin B (585 mg) which was prepared as in Example 2 (3) was~dissolve~d in methanol (7 ml), to which was added Raney nickel (R-100)(500 mg) and the mixture was stirred at room temperature (20C) for 2 hours. After the Raney nickel was removed by filtration, the filtrate was concentrated to dryness, affording the titled compound. Yield 450 mg (80%).
(2) Preparation of 3',4'-dideoxykanamycin B
3',4'-Dideoxy-3'-eno-penta-N-t-butoxy-4",6"-0-cyclohexylidene-kanamycin B (450 mg) was treated as ~ 39 .
5~
similar as in Example 1 (6) and (7), affording the titled compound. Yield 90%.
Example 6 (1) Preparation of 3'~4'-~-epoxy-penta~N-t-butoxycarbonyl-4",6" 0-cyclohexylidene-2"-0-benzoyl-kanamycin ~
3',4'-~-Epoxy-penta-N-t-butoxycarbony1-4",6"-0-cyclohexylidene-kanamycin B (2.0 g) was dissolved in dry pyridine (40 ml), to which was added benzoyl chloride (0.8 ml) under ice-cooling and the mixture was allowed to stand for reaction at 5C for 30 minutes. Then, water (2 ml) was added to the reaction mixture and~the mlxture~
; was concentrated to give a syrup which was then poured into water (20 ml) to form precipitate. The precipltate was recovered by filtration and dried to yield the kitled compound. Yield 2.16 g (98.3%).
`~ (2) Preparation o~ 4'-deoxy-4'-:iodo-penta-N-t-butoxy-carbonyl-4",6"-0-cyclohexylidene--2"-0-benzoyl-kanamycin B
3',4'-~-epoxy-penta-N-t-butoxycarbonyl-4",6"-0-cyclohexylidene-2"-0-benzoyl-kanamycin B (2.1 g) was dissolved in acetone (60 ml), to which were added sodium~
od~de (1.4 g), sodium acetate (80 mg) and glacial acetic acid~(1.4 ml) and the resulting mixture was refluxed~
for about 8 hours.
After the completion of the reaction, the mlxture was cooled to deposit crystals which were recovered by filtration. Yield 2.25 g (94%). mp. 171_176C (with ` decomposition).
Elementary analysis:
Found: C 52.81; H 7.11; N 5.31; I 10.39 Calculated for C~3H7 6 NsOlgI:
~ 6~ 6 C 52.62; H 6.94; N 5.48; I 9.93%
(3) Preparation of 3',4'-dideoxy-3'-eno-penta-N-t-butoXy-carbonyl-4",6"-0-cyclohexylidene-2"-0-benzoyl-kanamycin B
4?-Deoxy-4'-iodo-penta-N-t-butoxycarbonyl-4",6"-0-cyclohexylidene-2"-0-benzoyl-kanamycin B (452 mg) was dissolved in dry pyridine (9 ml), to which was added benæylsulfonyl chloride (305 mg) under cooling to 0~5C
for about 30 minutes.
After the completion of the reaction, methanol (0.18 ml) was addéd to the reaction mixture which was then heated to 90C for 50 minutes~ cooled to room tem-perature. The mixture was concentrated to a syrup, to which water (10 ml) was added to deposit crystals. The ; crystals were recovered by filtration and washed with water to obkain the titled compound in the form of a wet cake.
.
Identification of the compound thus obtained was made by silica-gel thin layer chromatography using carbon tetrachloride-acetone (4:1 by volume) as developer.
(4) Preparation of 3',4'-dideoxy-3'-eno-penta-N-t-~ butoxycarbonyl-4",6"-0-cyclohexylidene-kanamycin B~
; The wet cake of the compound obtained in the step (3) above was dissolved in methanol (20 ml), to which sodium methyla~e was added to adjust the pH to 9.0~10.0 and the mixture was stirred at room temperature for 30 minutes, neutralized with lN HCl and concentrated to a syrup. Addition of water to the syrup formed a precipitate which was recovered by filtration, washed with water arld dried to a~ford the titled compound.
Yield 360 mg (100%).
_ 41 .
3'4'-Dideoxy-3'-eno-kanamycin B (120 mg) was dissolved in water (4 ml), to which Raney nickel (0.2 ml) was added. Hydrogen was passed through the solution `
for 2 hours under atmospheric conditions of temperature ., . :
and pressure. After the catalys~ used was filte~red off, the ~iltrate was concentrated to dryness. Yield 108 mg `
(95%).
, ;~ 20 Example 2 (l~ Preparation of penta-N-t-butoxycarbonyl-kanamycin B
- Xanamycin B~(lO g) was added to a mixture of water (34 ml), triethylamine (24 ml) and dimethyl-Pormamide (48 ml). Then~ t-butyl-S-(4,6-dimethyl- ~
pyrimidin-2-yl)-thiol-carbonate (40 g) was added to the mixture at room temperature and the mixture was stirred at that temperature for 18 hours. Addition of water - (150 ml) to the mixture formed crystals which were re-covered by filtration and washed thoroughly with an aqueous saturated solution of ethyl acetate. Yield 20 . . .
~7~ii5~qE~ :
g (l00~). mp.229~~34C (decomposition with foaming).
Elementary analysis:
Found: C 52.61; H 7.86; N 6.93%
Calculated for C43H77NsO20:
C 52~47; H 7.90; N 7.12%
(2) Preparation of 3 t ~ 41-~-epoxy-penta-N~t-butoxy-carbonyl-4",6"-O-cyclohexylidene-kanamycin B
Penta-N-t-butoxykanamycln B (10 g) was treated in the same ways as those described in Example 1 (2), (3) and (4) above, yielding the titled compound. Yield 80%, ~a~2D ~ 27(c=l.O, pyrldine). mp. 232_234C
(decomposition with foaming).
(3) Preparation of 3',4'-episulfido-penta-N-t-butoxy-carbonyl-4",6"-O-cyclohexylidene-kanamycin B
3l~4'-~-Epoxy-penta-N-t-butoxyc~*x~yl-4~6~ ~ cyclo-hexylidene-kanamycin B (10 g) was suspended in n butanol 'l00 ml), to which was added potassium n-butylxanthate ~-(9 5 g) and the reaction was conducted at 90C for 2 hours. After the reaction was completed, the mixture was cooled and washed twice with l00 ml portions of water and the butanol layer separated was concentrated to dryness, affording a mixture comprising 3',4'-episulfido-penta-N-t-butoxycarbonyl-4",6~t-cyclohexylidene-kanamycin B and 3',4'-dideoxy-31-eno-penta-N-t-butoxy-carbonyl-4',6"-cyclohexylidene kanamycin B. Yield ll g.
The crude product was subjected to silica gel chromato-graphy using chloroform-methanol (50:l by volume) as developer, to isolate 31,4'-episulfido-penta-N-t-butoxy-carbonyl-4",6"-cyclohexylidene-kanamycin B. Yield 3.9 g (35%)- [~] D + 23 (c= l.0, pyridine). mp. 235~238C
(decomposition with foaming).
Elementary analysis:
Found: C 55.10; H 7.94; N 6.31; S 3.30%
Calculated for C~gH33NsOI8S:
C 55.39; H 7.89; N 6.59; S 3.02%
(4) Preparation of 3',4'-dideoxy-3'-eno-kanamycin B
3',4'-Episulfido-penta-N-t-butoxycarbonyl-4", 6"-0-cyclohexylidene-kanamycin B (1.15 g) was dissolved in methanol (12 ml)g to which was added concentrated ... .
10 hydrochloric acid (3 ml) and the reaction was conducted at room temperature for 3 hours.
The reaction mixture was concentrated to dryness and the resulting residue was dissolved in water (18 ml) and the pH of the solution was a~usted to 6.5 by the addition of lN sodium hydroxide solution (2.5 ml3.
The solution was passed through a column of 20 ml of Amberlite CG-50 (N~4+ form). The adsorbed column was washed with water and then O.lN aqueous ammonia and subsequently eluated with 0.3N aqueous ammonia. The concentration of the eluate gave the titled compound.
Yield 194 mg.
(5) Preparation o~f 3',4'-di~eoxykanamycin B
, .. . .
3'4'-Dideoxy-3'-eno-kanamycin B (120 mg) was dissolved in water (4~ml), to which was added Raney nickel (0.2 ml3 and hydrogen was passed through the mixture for 2 hours under atmospheric temperatùre and pressure ~conditions. After the catalyst was filtered off, the filtrate was concentrated to dryness, giving the tilted compound. Yield 108 mg (90%).
; 30 Example 3 * Trade ~Iark 7~ 6 Preparation of 3',4'-episulfido-penta-N-ethoxycarbonyl-4",6"-O-cyclohexylidene-kanamycin B
3',4'-~-Epoxy-penta-N-ethoxycarbonyl-4", 6 ~-o-~ cyclohexylidene-kanamycin B (100 mg) which was prepared : by the method described in Example l of DT-OS 2,555,479 was dissolved in pyridine (5 ml), to which was added potassium ethyl xanthate (100 mg) and the mixture was refluxed for l.5 hours and then concentrated to dryness.
A mixture of water and chloroform (2:3 by volume) was added to the solld residue and the chloroform layer was separated, was~hed three times with 20 ml portions of water and concentrated to dryness, yielding 70~mg of a crude product comprising 3',4'-episulfido-penta-N-ethoxycarbonyl-4",6"-O-cyclohexylidene-kanamycin B
and 3',4'-dideoxy-3'-eno-penta-N-ethoxycarbonyl-4",6"-O-cyclohexylidene~-kanamycin B.
The isolation of the respective compounds was carried out by thin layer chromatography ln the same manner as that used in Example 1 (5) above.
; 20 Example 4 ! (l) Preparation of 3',4l-dideoxy-3'-eno-penta-N-~ ~ !
ethoxycarbonyl-4",6"-O-cyclohexylidene~-kanamycin B
3',4'-Episulfido-penta-N-ethoxycarbonyl-4" ,6~-o-cyclohexylidene-kanamycin B (470 mg) which was prepared as described in Example l (5)(or Example 3tl)) above was dissolved in methanol (2 ml), to which was added hydrazine hydrate (0.22 ml) and the mixture was allowed to stand at room temperature for 2 hours. The reaction mixture was then concentrated to dryness and treated with water (20 ml) to form preclpitate which was re-` - 38 covered by filtration. Yield 362 mg (80%). [~]D
24.7 (c=l.0, methanol).
Elementary analysis:
Found: C 52.31; H 7.53; N 7.49%
Calculated for C3sH6 sNsOI a:
C 52.50; H 7.36; N 7.85%
(2) Preparation of 3',4'-dideoxy-3'-eno-kanamycin B
3',4~-Dideoxy-3 r -eno-penta-N-Ethoxycarbonyl-4'i, 6"-cyclohexylidene-kanamycin B (475 mg) was dissolved in methanol (5 ml) and treated in the same manner as that described in Example 1 (6), affordlng the titled compound.
; (3) Prepara~ion of 3',4'-dideoxykanamycin B
3',4'-Dideoxy-3i-eno-kanamycin B was treated as similar as in Example 1 (7), affording the titled compound.
Example 5 (1) Preparation of 3',4'-dideoxy-3'~-eno-penta-N-t-butoxy-4",6"-0-cyclohexylidene-kanamycin B
3',4'-Episul~ido-penta-N-t-butoxycarbonyl-4",6"-0-cyclohexylidene-kanamycin B (585 mg) which was prepared as in Example 2 (3) was~dissolve~d in methanol (7 ml), to which was added Raney nickel (R-100)(500 mg) and the mixture was stirred at room temperature (20C) for 2 hours. After the Raney nickel was removed by filtration, the filtrate was concentrated to dryness, affording the titled compound. Yield 450 mg (80%).
(2) Preparation of 3',4'-dideoxykanamycin B
3',4'-Dideoxy-3'-eno-penta-N-t-butoxy-4",6"-0-cyclohexylidene-kanamycin B (450 mg) was treated as ~ 39 .
5~
similar as in Example 1 (6) and (7), affording the titled compound. Yield 90%.
Example 6 (1) Preparation of 3'~4'-~-epoxy-penta~N-t-butoxycarbonyl-4",6" 0-cyclohexylidene-2"-0-benzoyl-kanamycin ~
3',4'-~-Epoxy-penta-N-t-butoxycarbony1-4",6"-0-cyclohexylidene-kanamycin B (2.0 g) was dissolved in dry pyridine (40 ml), to which was added benzoyl chloride (0.8 ml) under ice-cooling and the mixture was allowed to stand for reaction at 5C for 30 minutes. Then, water (2 ml) was added to the reaction mixture and~the mlxture~
; was concentrated to give a syrup which was then poured into water (20 ml) to form precipitate. The precipltate was recovered by filtration and dried to yield the kitled compound. Yield 2.16 g (98.3%).
`~ (2) Preparation o~ 4'-deoxy-4'-:iodo-penta-N-t-butoxy-carbonyl-4",6"-0-cyclohexylidene--2"-0-benzoyl-kanamycin B
3',4'-~-epoxy-penta-N-t-butoxycarbonyl-4",6"-0-cyclohexylidene-2"-0-benzoyl-kanamycin B (2.1 g) was dissolved in acetone (60 ml), to which were added sodium~
od~de (1.4 g), sodium acetate (80 mg) and glacial acetic acid~(1.4 ml) and the resulting mixture was refluxed~
for about 8 hours.
After the completion of the reaction, the mlxture was cooled to deposit crystals which were recovered by filtration. Yield 2.25 g (94%). mp. 171_176C (with ` decomposition).
Elementary analysis:
Found: C 52.81; H 7.11; N 5.31; I 10.39 Calculated for C~3H7 6 NsOlgI:
~ 6~ 6 C 52.62; H 6.94; N 5.48; I 9.93%
(3) Preparation of 3',4'-dideoxy-3'-eno-penta-N-t-butoXy-carbonyl-4",6"-0-cyclohexylidene-2"-0-benzoyl-kanamycin B
4?-Deoxy-4'-iodo-penta-N-t-butoxycarbonyl-4",6"-0-cyclohexylidene-2"-0-benzoyl-kanamycin B (452 mg) was dissolved in dry pyridine (9 ml), to which was added benæylsulfonyl chloride (305 mg) under cooling to 0~5C
for about 30 minutes.
After the completion of the reaction, methanol (0.18 ml) was addéd to the reaction mixture which was then heated to 90C for 50 minutes~ cooled to room tem-perature. The mixture was concentrated to a syrup, to which water (10 ml) was added to deposit crystals. The ; crystals were recovered by filtration and washed with water to obkain the titled compound in the form of a wet cake.
.
Identification of the compound thus obtained was made by silica-gel thin layer chromatography using carbon tetrachloride-acetone (4:1 by volume) as developer.
(4) Preparation of 3',4'-dideoxy-3'-eno-penta-N-t-~ butoxycarbonyl-4",6"-0-cyclohexylidene-kanamycin B~
; The wet cake of the compound obtained in the step (3) above was dissolved in methanol (20 ml), to which sodium methyla~e was added to adjust the pH to 9.0~10.0 and the mixture was stirred at room temperature for 30 minutes, neutralized with lN HCl and concentrated to a syrup. Addition of water to the syrup formed a precipitate which was recovered by filtration, washed with water arld dried to a~ford the titled compound.
Yield 360 mg (100%).
_ 41 .
Claims (10)
1. A process for the preparation of an intermediate used in the production of 3',4'-dideoxy-kanamycin B or its acid addition salts which comprises treating with a xanthate a 3',4'-epoxy derivative of an amino- and hydroxyl-protected kanamycin B of the formula (I) wherein R represents a hydrogen atom or an alkyl or aryl group, Z represents an alkylidene, arylidene, cyclo-hexylidene or tetrahydropyranylidene group and the 3', 4'-epoxy group is in .alpha.- or .beta.-position whereby to form a 3',4'-episulfido-kanamycin B derivative of the formula:
(III) wherein R and Z have the same meaning as defined above and the 3',4'-episulfide group is in .alpha.-or .beta.-position and isolating the 3',4'-episulfido-kanamycin B derivative from the reaction mixture.
(III) wherein R and Z have the same meaning as defined above and the 3',4'-episulfide group is in .alpha.-or .beta.-position and isolating the 3',4'-episulfido-kanamycin B derivative from the reaction mixture.
2. A process as claimed in Claim 1 wherein the xanthate is an alkali metal xanthate.
3. A process as claimed in Claim 1 wherein the treatment with a xanthate is carried out in an organic solvent.
4. A process as claimed in Claim 3 wherein the solvent is a lower alkanol.
5. A process as claimed in Claim 1 wherein the treatment with a xanthate is carried out at a temperature of 50°- 100°C.
6. A process as claimed in Claim 1 wherein R
represents ethyl and Z represents cyclohexylidene to produce 3',4'-episulfido-penta-N-ethoxycarbonyl-4",6"-O-cyclohexylidene-kanamycin B.
represents ethyl and Z represents cyclohexylidene to produce 3',4'-episulfido-penta-N-ethoxycarbonyl-4",6"-O-cyclohexylidene-kanamycin B.
7. A process as claimed in Claim 1 wherein R represents t-butyl and Z represents cyclohexylidene to produce 3',4'-episulfido-penta-N-t-butoxycarbonyl-4",6"-O-cyclohexylidene-kanamycin B.
8. A compound of the formula (III) wherein R represents a hydrogen atom or an alkyl or aryl group, Z represents an alkylidene, arylidene, cyclo-hexylidene or tetrahydropyranylidene group and the 3', 4'-episulfido group is in .alpha.- or .beta.-position, whenever produced by the process of Claim 1 or an obvious chemical equivalent there-of.
9. The compound 3',4'-episulfido-penta-N-ethoxycar-bonyl-4",6"-O-cyclohexylidene-kanamycin B whenever produced by the process of Claim 6 or an obvious chemical equivalent thereof.
10. The compound 3',4'-episulfido-penta-N-t-butoxy-carbonyl-4",6"-O-cyclohexylidene-kanamycin B whenever produced by the process of Claim 7 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA337,672A CA1076566A (en) | 1975-12-09 | 1979-10-16 | Processes for the preparation of 3',4'-dideoxykanamycin b |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14593075A JPS6029718B2 (en) | 1975-12-09 | 1975-12-09 | Production method of new derivative of kanamycin B |
| JP50146345A JPS6029719B2 (en) | 1975-12-10 | 1975-12-10 | New method for producing 3',4'-dideoxykanamycin B |
| CA267,236A CA1076564A (en) | 1975-12-09 | 1976-12-06 | Processes for the preparation of 3',4'-dideoxykanamycin b |
| CA337,672A CA1076566A (en) | 1975-12-09 | 1979-10-16 | Processes for the preparation of 3',4'-dideoxykanamycin b |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1076566A true CA1076566A (en) | 1980-04-29 |
Family
ID=27425959
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA337,672A Expired CA1076566A (en) | 1975-12-09 | 1979-10-16 | Processes for the preparation of 3',4'-dideoxykanamycin b |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1076566A (en) |
-
1979
- 1979-10-16 CA CA337,672A patent/CA1076566A/en not_active Expired
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