LV11180B - Diamine salts of clavulanic acid - Google Patents

Diamine salts of clavulanic acid Download PDF

Info

Publication number
LV11180B
LV11180B LVP-94-220A LV940220A LV11180B LV 11180 B LV11180 B LV 11180B LV 940220 A LV940220 A LV 940220A LV 11180 B LV11180 B LV 11180B
Authority
LV
Latvia
Prior art keywords
clavulanic acid
salt
diamine
pharmaceutically acceptable
ester
Prior art date
Application number
LVP-94-220A
Other languages
Latvian (lv)
Other versions
LV11180A (en
Inventor
Pieter Gijsbert Weber
Original Assignee
Gist Brocades Nv
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/EP1994/000919 external-priority patent/WO1994022873A1/en
Application filed by Gist Brocades Nv filed Critical Gist Brocades Nv
Publication of LV11180A publication Critical patent/LV11180A/en
Publication of LV11180B publication Critical patent/LV11180B/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D503/00—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D503/10—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
    • C07D503/12—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6
    • C07D503/14—Heterocyclic compounds containing 4-oxa-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxapenicillins, clavulanic acid derivatives; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 unsubstituted in position 6 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, other than a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, attached in position 3
    • C07D503/16—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical
    • C07D503/18—Radicals substituted by hetero atoms or by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical by oxygen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Description

LV 11180
DIAMINE SALTS OF CLAVULANIC ACID
The present invention relates to new diamine salts of clavulanic acid, pharmaceutical corapositions thereof, and to the use of these salts in the production of clavulanic acid and salts and esters thereof. GB patent 1508977 discloses that clavulanic acid, which has the formula (I):
(I) and its pharmaceutically acceptable salts and esters are anti-bacterial aģents, able to enhance the effectiveness of penicillins and cephalosporins against many /?-lactamase-producing bacteria. US patent 4,650,795 discloses a group of primary amine salts of clavulanic acid vhich give stable pharmaceutical compositions. EP patent 26044 discloses the use of the t-butylamine salt as a useful intermediate in the preparation of clavulanic acid.
The non-prepublished EP patent application 562583 discloses the same use for N,N-diisopropylethylenediammonium di clavulanate and N,N-diethylethylenediammonium di clavulanate, both of the secondary, secondary type.
Surprisingly it has been found that tertiary, tertiary diamine salts of clavulanic acid have improved properties compared to the t-butyl amine salt of clavulanic acid mentioned above. For instance, large crystals of the mono salt of Ν,Ν,Ν',Ν'-tetramethyl-l, 2-diaminoethane clavulanate can easily be precipi-tated in pure form. The salt is therefore a very useful intermediate in the preparation of clavulanic acid. 5 2
Accordingly, the present invention provides tertiary, tertiary diamine mono salts of the formula (Ila) : 5 2 10
H
C02“ Η—N— (CH2) n-C- (CH2) m NR2 I
X *3 R4 (Ila) 15 and tertiary/ tertiary diamine di salts of formula (Ilb): 20
:H2OH ch2oh,
25
h 0 1 Rl>v© I ®^r3 C02 - η—N— (CH2) n-c- (CH2) m—N—H r2 I r4 X
C02“ (Ilb) 3o where Rļ and R2 are each a (l-8C)alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group, optionally having one or more inert substituents or are interlinked to form a ring of 4-7 ring atoms; R2 and R4 are each a (l-8C)alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group, optionally having one or more 35 inert substituents or are interlinked to form a ring of 4-7 ring atoms; X is hydrogen or a hydrogen bridge forming group; and m and n are each, independently, 0-5.
An alkyl group may be branched or straight Chain. A C]_ to Cq alkyl group is preferably a C]_ to C4 alkyl group, 40 for example, methyl, ethyl, propyl, isopropyl, butyl, sec.butyl or tert.butyl, more preferably it is methyl. A C3 to Cg cycloalkyl group is preferably a C5 to C7 cyclo-alkyl group, for example cyclopentyl, cyclohexyl or cycloheptyl. - 3 - LV 11180
Preferably, X is hydrogen, hydroxy or halogen, for instance bromine or chlorine. Most preferably, X is hydrogen or hydroxy.
Preferablv n is from 0 to 3 and m is from 0 to 3, more preferably when X is hydrogen or hydroxy. Most preferably n = 1, m is 0 and X is hydrogen or n is 1, m is l and X is hydroxy.
Suitably inert substituents include halogen, hydroxy, Οχ to C4 alkyl, Οχ to C4 alkoxyl, Οχ to C4 acyloxyl and Οχ to C4 esterified carboxyl. A halogen atom is, for example, bromine, chlorine or fluor-ine, preferably, bromine or chlorine. A Οχ to C4 alkyl is preferably methyl or ethyl. A Οχ to C4 alkoxyl is preferably methoxyl or ethoxyl. A Οχ to C4 acyloxyl is preferably Οχ or Cļ acyloxyl. A Οχ to C4 esterified carboxyl is preferably Οχ or C2 esterified carboxyl.
Generally, Rx, R2, R3 and R4 have three substituents or fewer, preferably two substituents or fewer. Most preferably Rx, R2, R3 and R4 have one substituent or are unsubstituted.
When Rļ and R2 or R3 and R4 are interlinked to form a ring of 4 to 7 atoms, the ring consists preferably of carbon atoms and is most preferably saturated. Most preferably Rx, R2, R3 and R4 are methyl.
Normally the amine of the formula (III):
H r1n. I Λ >— (CH2) n-C- (CH2) m—N (III)
R2 I X
X from which the salts of the formulae (Ila) and (Ilb) are derivable is a pharmaceutically acceptable amine.
Preferably, the salts of the formulae (Ila) and (Ilb) are derivable from Ν,Ν,Ν',N/-tetramethyl-l,2-diaminoethane, lobīsi dimethylamino) -2-propanol, Ν,Ν,Ν' ,N'-tetramethvl-l,4-diamino-butane, Ν,Ν,Ν',N,-tetramethyl-l,6-diaminohexane, 1,2-dipiperidino-ethane and dipiperidinomethane. 4
The present invention also provides a process for the preparation of a salt of formulae (Ila) or (Ilb) which process coraprises the reaction of clavulanic acid with diamine (III):
H
Rl^. I /R3 ^ N— (CH2) n-C- (CH2) m—Νχ (III) Σ*2 I r4
X where R^, R2, R3, R4, X, m and n are as above defined. A diamine mono clavulanate will be formed when the amount of diamine is relatively high compared to that of clavulanic acid and the diamine di clavulanate will be formed when the amount of diamine is relatively low compared to that of clavulanic acid or a mixture of the same at a concentration in betveen.
The conditions when mono or diamine salts of clavulanic acid or a mixture of the same will be formed have not been investigated for each diamine, but it will be clear for someone skilled in the art that these will vary with the diamine applied.
The concentration of diamine present in the reaction mixture may be varied by, for example, varying the pH. At relatively high pH (dependent on the amine and the solvent used) more mono-protonated diamine (Illa):
H I /1*3 Η—N— (CH2)n-C-(CH2)m—N (Illa) R2 I R4
X will be present and therefore more mono salt will be precipitated, and at relatively low pH more di-protonated diamine (Illb):
H r1-JB I ®^r3 Η—N— (CH2) n-0- (CH2) m—N—H (IHb) r/ I r4
X will be present and therefore more di salt will be precipitated. - 5 LV 11180
The present invention further provides the use of diamine salts of clavulanic acid as defined above as an intermediate in the preparation of clavulanic acid and a pharmaceutically accept-able salt or ester thereof.
In another aspect the present invention provides a process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof which process comprises convert-ing a diamine salt of clavulanic acid as defined above into clavulanic acid, generally by acidif ication, or a pharmaceutically acceptable salt or ester thereof, generally by adding a source of corresponding salt or ester forming compound.
In a further aspect the present invention provides a process for the purification of clavulanic acid or a pharmaceutically acceptable salt or ester thereof which process comprises: i) contacting impure clavulanic acid in an organic solvent with diamine to form a salt; ii) isolating the salt produced in step i); and iii) converting the isolated salt into clavulanic acid, generally by acidif ication, or a pharmaceutically acceptable salt or ester thereof, generally by adding a source of a corresponding salt or ester forming compound. For instance, potassium clavula-nate is formed by adding potassium acetate or potassium ethyl-hexanoate.
Most suitably the formation of the diamine salts of clavulanic acid takes place in an organic solvent. Suitable solvents include non-hydroxylic solvents such as, for example, tetrahydro-furan, dioxane, ethyl acetate, methyl acetate, acetone, methyl-ethylketone and the like solvent and mixtures thereof.
The reaction may be carried out at from about -50*C to 40*c, most preferably from about 0*C to 15*C.
The present invention also provides pharmaceutical composi-tions which comprise a salt of the formulae (Ila) and/or (Ilb) and a pharmaceutically acceptable carrier.
Suitable forms of the compositions of this invention include tablets, capsules, reconstitutable powders and sterile forms suitable for injection or infusion. Such compositions may contain conventional pharmaceutically acceptable materiāls such as 6 diluents, binders, colours, flavours, preservatives and disinte-grants.
Injectable or infusible compositions of the salts of formulae (Ila) and (Ilb) are particularly suitable as high tissue Ievels 5 of the compound of clavulanic acid can occur after administration by injection or infusion. Thus, one preferred composition aspect of this invention com^rises salts of the formulae (Ila) and (Ilb) in sterile form.
Unit dose compositions comprising a salt of the formula (II) 10 adapted for oral administration form a further preferred composition aspect of this invention.
The folloving examples will illustrate the invention. The pH value mentioned relates to this value measured with an Ingold electrode, type U402-S7/120, in the solvents applied. - 7 - LV 11180
Examples Example 1
Comparison of crystallization of various diamine salts A solution of potassium clavulanate in ice cold water was stirred with ethyl acetate under cooling with ice-water. With a solution of about 10% (w/w) sulphuric acid the pH was brought at about 2, the water layer separated and twice extracted with ethyl acetate. The collected extracts were dried with magnesium sulphate, filtered and vashed with ethyl acetate, yielding a solution of clavulanic acid of about 2% (w/w) . The clavulanic acid was diluted with an equal volume of acetone and diamine was added.
The results are summarized in Table I. The ratio moles diamine/moles clavulanic acid has been indicated in the last column. The tertiary, tertiary type diamine salts of clavulanic acid are present in the preferred crystal form only, viz. not in the form of an oil.
Table Z
Diamine type1 crystals oil diamine Ν,Ν,Ν',N'-tetramethyl-l,2-di-aminoethane t,t + - 1.90 Ν,Ν,Ν',N/-tetramethyl-l,2-di-aminoethane t,t + - 0.68 Ν,Ν,Ν',N'-tetramethyl-l,3-di-aminopropane t,t + - 1.89 1,3-bis(dimethylamino)-2-propanol t,t + _ 1.74 Ν,Ν,Ν',N'-tetramethyl-l,4-di-aminobutane t,t + - 1.34 Ν,Ν,Ν',N'-tetramethyl-l, 6-di-aminohexane t,t + - 1.84 1,2-dipiperidinoethane t,t + - 2.70 δ T&ble X, continued
Diamine type1 crystals oil diamine 1,2-diaminoethane P/P + + 3.98 1,3-diaminopropane P,P + + 1.69 1,6-diaminohexane P/P — + 1.69 1,10-diaminodecane P/P - + 1.46 N-methyl-l,3-diaminopropane P/S - + 1.69 N,N-dimethyl-l,3-diaminopropane p,t - + 1.86 N,N-dimethyl-l,2-diaminoethane P/t - + ļ 1.69 piperazine s, s - + 1.20 N-methylpiperazine S,t I + 1.20 N,N-diethyl-l,2-diaminoethane P/t — - 0.81 N-(2-aminoethyl)-morfoline P/t - 1.20 dipiperidinomethane t,t + - 14.92 1 p: primary; s: secondary; t: tertiary
Example 2
Preparation of Ν,Ν,Ν' , Ν'-tetramethy 1-1,2-diaminoethane mono clavulanate from ethyl acetate/acetone solution A clavulanic acid extract in dry ethyl acetate (828 g containing 18 g of clavulanic acid/kg prepared according to example 1) was added in 20 min to 1 1 of acetone while cooling (8 *C) and keeping the pH at 9 with Ν,Ν,Ν' , N'-tetramethyl-l, 2-diaminoethane (TMEDA, 19.18 g, viz. a molar ratio of 2.2 related to clavulanic acid). Stirring was continued at 10*C for 1 hr. The precipitate was filtered off and vashed with 100 ml of acetone and dried in vacuum at 35*C to yield 20.09 g of TMEDA mono clavu-lanate (large crystals) . The mother liguor (1642 g) contained about 1.12 g of clavulanic acid. NMR (DMSO-d6) : 2.37 ppm, N-CH3 (s, 12H) 7 2.70 ppm, N-CH2 (s, 4H) ; 2.95 ppm, C6-/3H (d, 1H) ; 3.49 ppm, C6-aH (dd, 1H) ; LV 11180 - 9 - 3.99 ppm, CH2OH (m, 2H) ; 4.60 ppra, C3-H (s, 1H) ; 4.66 ppm, =C-H (tr, 1H); 5.58 ppm, C5-H (d, 1H).
To 1 g of this TMEDA mono clavulanate 200 ml of a mixture of ethyl acetate/acetone (1/1 v/v) comprising 1 ml of TMEDA was added. After stirring during 1 hr at room temperature and filtrat-ing the solution, the filtrate was slowly evaporated, resulting in large crystals.
Ali parameters were obtained by least sguares from 2 Θ values for reflections measured on a diffractometer under the folloving experimental conditions: CAD 4 Rf Nonius Θ = 30*
Mo-Kot radiation λ = 0.70145 A.
The salt (^41^5^05, group 1 C3H9NO5 and group 2 Mw = 315.37) crystallizes in the orthorhombic space group Ρ2χ2ι2ι with a = 8.268(1), b = 9.929(7) and c = 20.221(2) A. a, β and y = 90*. R = 0.206 for 2747 reflections. Z = 4.
The molecules are bonded via a strong hydrogen bond (2.65(1) A) between N(2) and 0(3). The 0(6)-0(2) and 0(6)-0(3) distances are 1.20(1) and 1.275(9) A, respectively, indicating a partial single bond character between 0(6)-0(3).
The atom coordinates are shown in Table II:
Table II x/a y/t> z/c sigx sigy ! sigz C1 .73451 .61143 .51083 .00109 .00094 ! .00039 C2 .72822 .73554 .46864 .00099 .00085 ; .00037 C3 .77712 .80814 .53160 .00099 .00091ļ .00038 04 .62466 .80092 .62729 .00091 .00081 ! .00035 C5 .74057 .68316 .63023 .00092 .00079 , .00033 06 .87476 .71031 .68279 .00092 .00083 ! .00034 C7 .51426 .83929 .67005 . 00099 .00089 .00039 10 T&ble II/ continued x/a y/b z/c sigx sigy sigz C8 .40390 .95903 .66482 .00104 .00092 .00040 C9 .94385 .09742 . 62131 .00161 .00119 .00049 CIO .77651 .20910 .70628 .00115 .00169 .00053 Cll 1.36988 .31842 .57368 .00165 .00182 .00077 C12 1.28231 .43860 .66215 .00211 .00137 .00068 C13 1.07802 .36142 .57942 .00185 .00171 .00077 C14 .92742 .34721 .63555 .00146 .00127 .00064 N2 .92914 .21251 .66938 .00078 .00080 .00031 N3 1.22359 .33641 .61693 .00112 .00091 .00037 01 .69320 .49552 .50870 .00079 .00072 .00030 02 .98843 .77785 .66617 .00065 .00064 .00027 03 .84583 .65805 .73917 .00070 .00070 .00025 04 .64046 .86534 .56720 .00068 .00060 .00026 05 .42783 1.04139 .72369 .00074 .00075 .00031 N1 .80549 .68028 .56442 .00069 .00067 .00028 H21 .82775 .76503 .43642 .00679 .00618 .00278 H22 .60667 .74308 .44395 .00696 .00637 .00278 H31 .87967 .86532 .53289 .00739 .00655 .00279 H51 .69414 .59219 .64269 .00759 .00616 .00283 H71 .51235 .78214 .69945 .00721 .00654 .00273
Example 3 25 Preparation of N/N,N'/N/-tetramethyl-l/2-diaminoethane mono clavulanate from etbyl acetate solution A solution of clavulanic acid in ethyl acetate (75 g, con-taining about 20 g of clavulanic acid/kg) was added in 10 min 30 to 75 ml of ethyl acetate at 8*C while stirring and keeping the pH betveen 8 and 9 with N, N, N', N' -tetramethy 1 -1,2 -diaminoethane (TMEDA, 5.11 g, viz. a molar ratio of 8 related to clavulanic acid) . Stirring was continued for 0.5 hr and the precipitate was filtered off, vashed with ethyl acetate and dried in vacuum at 35 35*C to give 2.62 g of TMEDA mono clavulanate (large crystals) .
The mother liquor (155 g) contained 0.03 g of clavulanic acid. NMR (DMS0-d6): 2.38 ppm, N-CH3 (s, 12H); 2.70 ppm, N-CH2 (s, 4H) ; 2.93 ppm, C6-/3H (d, 1H) ; 3.48 ppm, C6-aH (dd, 1H) ; 3.98 ppm, CH20H (m, 2H) ; 4.58 ppm, C3-H (s, 1H) ; 4.65 ppm, =C-H 40 (tr, 1H); 5.58 ppm, C5-H (d, 1H). - 11 - LV 11180
Eacample 4
Preparation of Ν,Ν,Ν'/N/-tetramethyl-l,2-dianiinoethane di clavulanate from ethyl acatate/acetone solution A solution of clavulanic acid in ethyl acetate (200 ml con-taining 1.1 g of clavulanic acid) was added in 10 min to 200 ml of cold acetone (10*C) while stirring and keeping the pH betveen * 7.5 and 8 with Ν,Ν,Ν' ,N'-tetramethyl-l,2-diaminoethane (TMEDA, 0.64 g, viz. a molar ratio of 1.45 related to clavulanic acid). Stirring was continued for 0.5 hr and the precipitate was filtered off, vashed with acetone and dried in vacuum at 35*C to give 1.24 g of TMEDA di clavulanate (crystals in needle form). The mother liquor (337 g) contained 0.11 g of clavulanic acid. NMR (DMSO-d6): 2.45 ppm, N-CH3 (s, 12H); 2.80 ppm, N-CH2 (s, 4H) ; 2.99 ppm, C6-0H (d, 2H) ; 3.53 ppm, C6-aH (dd, 2H) ; 3.99 ppm, CH2OH (m, 4H) ; 4.69 ppm, =C-H (tr, 2H) ; 4.76 ppm, C3-H (s, 2H); 5.61 ppm, C5-H (d, 2H) .
Example 5
Preparation of 1,3-bis (dimethylaaino) -2-propanol aono clavulanate A solution of clavulanic acid in ethyl acetate (100 g, con-taining 20 g clavulanic acid/kg) was added over a period of 10 min to 100 ml of acetone while stirring at 8*C and keeping the pH between 8.5 and 8.7 with 1,3-bis(dimethylamino)-2-propanol (2.54 g, viz. a molar ratio of 1.74 related to clavulanic acid) . Stirring was continued for 0.25 hr and the precipitate was filtered off and washed with 50 ml of a 1/1 mixture of acetone and ethyl acetate and with acetone. Drying in vacuum at room temperature yielded 1.82 g of 1,3-bis (dimethylamino) -2-propanol mono clavulanate with a purity of 25.6% as free acid. NMR (DMSO-d6): 2.41 ppm, N-CH3 (s, 12H); 2.50 ppm, N-CH2 (čLABg, 4H, J 12.6 Hz, J 4.8 Hz) ; 2.61 ppm, N-CH2 (dABq, 4H, J 12.6 Hz, J 4.8 Hz) ; 2.94 ppm, C6-/JH (d, 1H, J 16.5 Hz) ; 3.49 ppm, C6-aH (dd, 1H, J 16.5 Hz, J 2,7 Hz); 3.96 ppm CH20H, CHOH (m, 12 3Η) ; 4.58 ppm, C3-H (s, 1Η) ; 4.64 ppm =C-H (tr, 1H, J 6.8 Hz) ; 5.57 ppm, C5-H (d, 1H, J 2.6 Hz) .
Example 6
Conversion of Ν,Ν,Ν' ,N'-tetraaethyl-l,2-diaainoethane mono clavulanate into potassium clavulanate 30 ml of a 0.35 M potassium acetate solution (solvent isopro-pylalcohol and 1% (w/v) water) was added dropvise to a suspension of 2 g of Ν,Ν,Ν',Ν'-tetramethyl-l, 2-diamminoethane mono clavulanate (content 68.6%) in 50 ml of isopropanol. After 0.7 5 hr stirring at room temperature the precipitate was filtered, vashed with 10 ml of isopropanol and dried in vacuum at 35*C yielding 1.44 g of crystalline potassium clavulanate with a content of 87% (clavulanic acid) and about 1.5% potassium acetate (HPLC analysis) . The mother liquor contained about 0.06 g of clavulanic acid.
Ezample 7
Conversion of Ν,Ν,Ν' ,N'-tetramethyl-l,2-diaminoethane di clavulanate into potassium clavulanate 4.5 ml of a 2M solution of potassium 2-ethyl-hexanoate in isopropanol was added to a stirred solution of 2 gofN,N,N',N'-tetramethyl-l,2-diaminoethane di clavulanate (purity 75.8% calculated as the free acid) in 20 ml of isopropanol and 2 ml of water at room temperature. After stirring for 0.25 hr the precipitate was filtered off and vashed vith 5 ml of isopropanol. Drying in vacuum at room temperature gavē 0.30 g of potassium clavulanate with a purity of 83.6% calculated as the free acid. A further 2.5 ml of a 2M solution of potassium 2-ethyl-hexanoate in isopropanol vas added to the mother liquor and stirring vas continued. The precipitate vas filtered off, vashed vith 5 ml of isopropanol and dried to give 0.68 g of potassium clavulanate vith a purity of 82.3% calculated as the free acid. - 13 - LV 11180
Example 8
Conversion of 1,3-bis (diaethylami.no) -2-propanol mono clavulanate into potassium clavulanate 5 1.6 ml of a 2M solution of potassium 2-ethyl-hexanoate in isopropanol was added to a stirred solution of 1 g of 1,3-bis(di-methylamino)-2-propanol mono clavulanate in 19 ml of isopropanol and 1 ml of water at room temperature. After stirring for 0.25 hr the precipitate was filtered off and vashed with 15 ml of iso-io propanol. Drying in vacuum at room temperature gavē 0.38 g of potassium clavulanate with a purity of 80% as free acid. - 14 - LV 11180
Claims 1. A salt of clavulanic acid of the formula (Ila) or (Ilb) :
C02‘
H 10 I Λ Η—N— (CH2) n-C- (CH2) m—N. R2 I «4
X 15 (Ila)
(Ilb) where R^ and R2 are each a (l-8C)alkyl, (3-8C)cycloalkyl or 30 (3-8C)cycloalkyl(1-8C)alkyl group, optionally having one or more inert substituents or are interlinked to form a ring of 4-7 ring atoms; R3 and R4 are each a (l-8C)alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl group, optionally having one or more inert substituents or are interlinked to form a ring of 4-7 ring 35 atoms; X is hydrogen or a hydrogen bridge forming group; and m and n are each, independently, 0-5. 2. A salt of clavulanic acid according to claim 1 where R]_, R2, R3 and R4 are methyl. . 3. A salt of clavulanic acid according to claim 1 or 2 where X is hydrogen, n is 1 and m is 0. 15 4. A salt of clavulanic acid according to claim 1 or 2, vherein X is hydroxy, n is 1 and m is l. 5. A mono salt of clavulanic acid of formula Ila according to claim 1, vherein Rļ, R2, R3 and R4 are methyl, X is hydrogen, n is l and m is 0. 6. A process for preparing a salt as claimed in claim 1, 2, 3 or 4, vherein clavulanic acid is reacted vith a diamine (III):
H *1^ 1 Λ >— (CH2)n-C-(CH2)m—I» (III) R2 I ^4
X vherein R2, R3, R4, X, m and n are as defined in claim 1, 2, 3 or 4, in an organic solvent. 7. A process according to claim 6 vherein the molar amount of diamine is greater than that of clavulanic acid. 8. A process according to claim 6 vherein the molar amount of diamine is less than that of clavulanic acid. 9. A process to prepare a salt as claimed in claim 5, vherein clavulanic acid is reacted vith Ν,Ν,Ν',N'-tetramethyl-l, 2-diamino-ethane vherein the molar amount of Ν,Ν,Ν' ,N'-tetramethyl-l,2-diaminoethane is greater than that of clavulanic acid. 10. A process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof vhich comprises converting a mono or diamine salt as claimed in claim 1, 2, 3 4 and 5 into clavulanic acid or a pharmaceutically acceptable salt or ester thereof. - 16 - LV 11180 11. A process for the purification of clavulanic acid or a phannaceutically acceptable salt or ester thereof which process comprises: i) containing impure clavulanic acid in an organic solvent with diamine of formula III to form a salt; ii) isolating the salt produced in step i); and iii) converting the isolated salt into clavulanic acid or a pharmaceutically acceptable salt or ester thereof. 12. A pharmaceutical composition comprising a salt of clavulanic acid as claimed in claim 1, 2, 3, 4 or 5 and a pharmaceuti-cally acceptable carrier or diluent. 13. Use of a salt as claimed in claim 1, 2, 3, 4 or 5 as an intermediate in a process for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof. 14. A clavulanic salt substantially as described in any one of Examples 2 to 8. 15. A process for preparing a diamine salt of clavulanic acid from clavulanic acid substantially as described in any one of Examples 2, 3, 4 and 5. 16. A process for preparing clavulanic acid from a diamine salt thereof substantially as described in any one of Examples 6, 7 and 8.

Claims (16)

LV 11180 IZGUDROJUMA FORMULA KLAVULĀNSKĀBES SĀLI AR DIAMĪNU « 1. Klavulānskabes sals, kas atbilst formulai (lla) vai (llb):EN 11180 INVENTORY FORMULA CLAVULAR SALT SALT WITH DIAMINE «1. A clavulan-like frost corresponding to formula (IIa) or (IIb): (llb) kur katrs no R-ļ un R2 ir (1-8C)alkil-, (3-8C)cikloalkil- vai (3-8C)cikloalkil (1-8C) alkilgrupa, vēlams ar vienu vai vairākiem inertiem aizvietotājiem, vai saistīti savā starpā un izveido gredzenu ar 4-7 atomiem ciklā; katrs no R3 un R4 ir (1-8C)alkil-, (3-8C)cikloalkil- vai (3-8C)cikloalkil (1-8C)alkilgrupa, vēlams ar vienu vai vairākiem inertiem aizvietotājiem, vai saistīti savā starpā un izveido gredzenu ar 4-7 atomiem ciklā; X ir ūdeņraža atoms vai grupa, kas veido ūdeņraža tiltiņu; un katrs no n un m ir 0-5, neatkarīgi viens no otra.(IIb) wherein each of R 1 and R 2 is (1-8C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl, preferably with one or more inert substituents, or link each other and form a ring with 4-7 atoms per cycle; each of R 3 and R 4 is (1-8C) alkyl, (3-8C) cycloalkyl or (3-8C) cycloalkyl (1-8C) alkyl, preferably with one or more inert substituents, or linked to one another and to form a ring with 4-7 atoms per cycle; X is a hydrogen atom or a group forming a hydrogen bridge; and each of n and m is 0-5 independently of one another. 2. Klavulānskābes sāls, saskaņā ar 1. punktu, kas atšķiras ar to, ka R-ļ, R2, R3 un R4 ir metilgrupa. 2A clavulanic acid salt according to claim 1, wherein R 1, R 2, R 3 and R 4 are methyl. 2 3. Klavulānskābes sāls, saskaņa ar 1. vai 2. punktu, kas atšķiras arto, ka X ir ūdeņraža atoms, n ir 1 un m ir 0.3. Clavulanic acid salt according to claim 1 or 2, wherein X is hydrogen, n is 1 and m is 0. 4. Klavulānskābes sāls, saskaņā ar 1. vai 2. punktu, kas atšķiras arto, ka X ir hidroksilgrupa, n ir 1 un m ir 1.4. Clavulanic acid salt according to claim 1 or 2, characterized in that X is hydroxy, n is 1 and m is 1. 5. Formulas lla diamīna sāls ar vienu klavulānskābes molekulu, saskaņā ar 1. punktu, kas atšķiras ar to, ka R-ļ, R2, R3 un R4 ir metilgrupas, X ir ūdeņraža atoms, n ir 1 un m ir 0.5. Formula III diamine salt with one clavulanic acid molecule according to claim 1, characterized in that R 1, R 2, R 3 and R 4 are methyl, X is hydrogen, n is 1 and m is 0. 6. 1., 2., 3. vai 4. punktā aprakstītā sāls iegūšanas paņēmiens, kas atšķir a s arto, ka klavulānskābe reaģē ardiamīnu (III): R, V A \ I / N-(CHJn - C—(CHj)m-N X A R1, R2, R3, R4, X, m un n ir tādi kā norādīts 12., 3. vai 4 punktā, organiskā šķīdinātājā.6. A process for preparing a salt as described in claim 1, 2, 3, or 4, wherein the clavulanic acid reacts with ardiamine (III): R, VA I / N- (CH 2n - C (CH 1) mN X A R 1, R 2, R 3, R 4, X, m and n are as defined in points 12, 3 or 4 in an organic solvent. 7. Paņēmiens, saskaņā ar 6. punktu, kas atšķiras ar to, ka diamīna molu daudzums ir lielāks nekā klavulānskābes molu daudzums.7. A method according to claim 6, wherein the amount of diamine moles is greater than the amount of clavulanic acid moles. 8. Paņēmiens, saskaņā ar 6. punktu, kas atšķiras ar to, ka diamīna molu daudzums ir mazāks nekā klavulānskābes molu daudzums.8. A method according to claim 6, wherein the amount of diamine moles is less than the mole of clavulanic acid. 9. Sāls iegūšanas paņēmiens, saskaņā ar 5. punktu, kas atšķitras arto, ka klavulānskābe reaģē ar N, N, Ν', Ν' - tetrametil -1,2 - diaminoetānu un N, N, Ν’, Ν’ -tetrametil - 1,2 - diaminoetāna molu daudzums ir lielāks nekā klavulānskābes molu daudzums.9. The salt process according to claim 5, wherein the clavulanic acid reacts with N, N, Ν ', Ν' - tetramethyl-1,2-diaminoethane and N, N, Ν ', Ν' -tetramethyl. The amount of 1,2-diaminoethane moles is higher than the amount of clavulanic acid moles. 10. Klavulānskābes vai tās farmaceitiski pieņemama sāls vai estera sagatavošanas paņēmiens, kurā ietilpst mono-, vai diamīna sāls, kas aprakstīts 1., 2., 3., 4. un 5. punktā, pārvēršana par klavulānskābi vai tās farmaceitiski pieņemamu sāli vai esteri.A process for preparing a clavulanic acid, or a pharmaceutically acceptable salt or ester thereof, comprising converting the mono- or diamine salt described in paragraphs 1, 2, 3, 4 and 5 into clavulanic acid or a pharmaceutically acceptable salt or ester thereof. . 11. Klavulānskābes vai tās farmaceitiski pieņemama sāls vai estera attīrīšanas paņēmiens, kurā ietilpst: i) sāls veidošanās no neattīrītas klavulānskābes organiskā šķīdinātājā ar formulas III diamīnu; ii) stadijā i) iegūta sāls izdalīšana; un iii) izolētā sāls pārvēršana par klavulānskābi, tās farmaceitiski pieņemamu sāli vai esteri.A process for purifying clavulanic acid or a pharmaceutically acceptable salt or ester thereof, comprising: i) forming a salt from the crude clavulanic acid in an organic solvent of the formula III diamine; ii) isolating the salt obtained in step i); and iii) converting the isolated salt to clavulanic acid, a pharmaceutically acceptable salt or ester thereof. 12. Farmaceitiska kompozīcija, kurā ietilpst klavulānskābes sāls, saskaņā ar 1., 2., 3., 4. vai 5. punktu un farmaceitiski pieņemama pildviela vai atšķaidītājs.12. A pharmaceutical composition comprising a clavulanic acid salt according to claim 1, 2, 3, 4 or 5 and a pharmaceutically acceptable excipient or diluent. 13. Sāls, saskaņā ar 1., 2., 3., 4. vai 5 punktu, izmantošana par starpproduktu klavulānskābes vai tās farmaceitiski pieņemama sāls vai estera iegūšanas procesā. LV 11180 3Use of a salt according to claim 1, 2, 3, 4 or 5 as an intermediate for the preparation of clavulanic acid or a pharmaceutically acceptable salt or ester thereof. LV 11180 3 14. Klavulānskābes sāls pēc būtības, kā aprakstīts jebkurā no 2. līdz 8. piemēram.14. A salt of clavulanic acid as described in any one of claims 2 to 8. 15. Klavulānskābes sāls ar diamīnu iegūšanas paņēmiens no klavulānskābes pēc būtības, kā aprakstīts jebkurā no piemēriem 2., 3., 4. un 5.A process for the preparation of a clavulanic acid salt with diamine by the nature of clavulanic acid as described in any of the examples 2, 3, 4 and 5. 16. Klavulānskābes iegūšanas paņēmiens no tās sāls ar diamīnu pēc būtības, kā aprakstīts jebkurā no piemēriem 6., 7. un 8.A process for the preparation of clavulanic acid from its salt with diamine as described in any of the Examples 6, 7 and 8.
LVP-94-220A 1993-03-26 1994-11-22 Diamine salts of clavulanic acid LV11180B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP93200872 1993-03-26
PCT/EP1994/000919 WO1994022873A1 (en) 1993-03-26 1994-03-22 Diamine salts of clavulanic acid

Publications (2)

Publication Number Publication Date
LV11180A LV11180A (en) 1996-04-20
LV11180B true LV11180B (en) 1996-08-20

Family

ID=8213723

Family Applications (1)

Application Number Title Priority Date Filing Date
LVP-94-220A LV11180B (en) 1993-03-26 1994-11-22 Diamine salts of clavulanic acid

Country Status (8)

Country Link
JP (1) JP2839955B2 (en)
KR (1) KR100187333B1 (en)
BG (1) BG61948B1 (en)
BR (1) BR9404743A (en)
GR (2) GR950300030T1 (en)
LV (1) LV11180B (en)
RU (1) RU2135502C1 (en)
SI (1) SI0647229T1 (en)

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1578739A (en) * 1976-07-23 1980-11-05 Beecham Group Ltd Amine salts of clavulanic acid methods for their preparation and compositions containing them
AT399155B (en) * 1992-03-26 1995-03-27 Lek Tovarna Farmacevtskih NEW ALKYLENE DIAMMONIUM DICLAVULANATE DERIVATIVES, METHOD FOR THE PRODUCTION AND USE THEREOF

Also Published As

Publication number Publication date
BG61948B1 (en) 1998-10-30
RU94046014A (en) 1996-10-10
BG99212A (en) 1995-12-29
KR950701635A (en) 1995-04-28
RU2135502C1 (en) 1999-08-27
KR100187333B1 (en) 1999-05-01
GR950300030T1 (en) 1995-06-30
BR9404743A (en) 1999-09-28
GR3021347T3 (en) 1997-01-31
LV11180A (en) 1996-04-20
JP2839955B2 (en) 1998-12-24
SI0647229T1 (en) 1997-10-31
JPH07507573A (en) 1995-08-24

Similar Documents

Publication Publication Date Title
EP0647229B1 (en) Diamine salts of clavulanic acid
KR20170007304A (en) Carotenoid derivative, pharmaceutically acceptable salt thereof, and pharmaceutically acceptable ester or amide thereof
IE56488B1 (en) Crystalline cephem-acid addition salts and process for their preparation
US4456753A (en) Process for the manufacture of highly crystalline sodium cefoperazone
SU845789A3 (en) Method of preparing d-7-/alpha-(4-oxy-6-methylnicotineamido)-alpha-(4-oxyphenyl)-acetamido/-3-(1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid
SK111197A3 (en) Clavulanic acid salts
US5821364A (en) Diamine salts of clavulanic acid
HU207087B (en) Process for producing crystalline acid addition salts of cefemcarboxylic acid
PT93571B (en) (S) -7- (3-AMINO-1-PYRROLIDINYL) -1-CYCLOPROPYL-6-FLUORO-1,4-DIHYDRO-4-OXO-1,8-NAFTIRIDINE-3-CARBOXYLIC ACID AND METHOD FOR THE PREPARATION OF OF PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT
AU702968B2 (en) Clavulanic acid salts
EP0400499B1 (en) Medicine containing acylaminoacid derivatives and dietetic products
LV11180B (en) Diamine salts of clavulanic acid
DE1795151B2 (en) 7-square bracket on D-alpha-amino- (3-actamidophenylacetamido) square bracket on -cephalosporanic acid
US5760218A (en) Diamine salts of clavulanic acid
US5302588A (en) Crystalline (5R,6S)-2-carbamoyloxymethyl-6-[(1R)-hydroxyethyl]-2-penem-carboxylic acid and its pharmaceutical formulation
IE61325B1 (en) Crystalline salts of [3s(z)]-2[[[1-(2-amino-4-thiazolyl)-2-[[2,2-dimethyl-4-oxo-1 -(sulfooxy)-3-azetidinyl]amino]-2-oxoethylidene] amino]oxy]acetic acid
JPH066591B2 (en) Mitomycin derivative and antitumor agent
US5741903A (en) Diamine salts for purification of clavulanic acid
WO2023201707A1 (en) Process for chemical synthesis of ergothioneine and methods of use
IL37224A (en) Pharmaceutical compositions containing 3-acyloxypropyl-2-(trimethylammonium)-ethyl phosphates
CA2247329C (en) Composition containing antitumor agent
GB1581834A (en) Complexes of barbituric acid derivatives
KR20020031391A (en) A process for the synthesis of beta-lactam derivatives
GB2144423A (en) 1-Methyl-5-nitro-imidazole derivatives
JPS6150950B2 (en)