GB1571765A - Tetracycline derivatives - Google Patents
Tetracycline derivatives Download PDFInfo
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- GB1571765A GB1571765A GB1342878A GB1342878A GB1571765A GB 1571765 A GB1571765 A GB 1571765A GB 1342878 A GB1342878 A GB 1342878A GB 1342878 A GB1342878 A GB 1342878A GB 1571765 A GB1571765 A GB 1571765A
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- Prior art keywords
- methylene
- tetracycline
- butyl
- mixture
- deoxy
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- 239000004098 Tetracycline Substances 0.000 title claims description 45
- 235000019364 tetracycline Nutrition 0.000 title claims description 45
- 229960002180 tetracycline Drugs 0.000 title claims description 23
- 229930101283 tetracycline Natural products 0.000 title claims description 23
- 150000003522 tetracyclines Chemical class 0.000 title description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 38
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 24
- 239000000203 mixture Substances 0.000 claims description 23
- 125000001475 halogen functional group Chemical group 0.000 claims description 22
- 229940040944 tetracyclines Drugs 0.000 claims description 22
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 16
- 238000000034 method Methods 0.000 claims description 16
- 238000006297 dehydration reaction Methods 0.000 claims description 13
- 150000002825 nitriles Chemical class 0.000 claims description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 230000018044 dehydration Effects 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 229960000583 acetic acid Drugs 0.000 claims description 8
- 239000012362 glacial acetic acid Substances 0.000 claims description 8
- 239000011541 reaction mixture Substances 0.000 claims description 8
- 239000001117 sulphuric acid Substances 0.000 claims description 8
- 235000011149 sulphuric acid Nutrition 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 125000005518 carboxamido group Chemical group 0.000 claims description 7
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 239000012442 inert solvent Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- -1 t - butyl Chemical group 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- 239000000047 product Substances 0.000 claims description 3
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 238000009877 rendering Methods 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000002026 chloroform extract Substances 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 230000003472 neutralizing effect Effects 0.000 claims 1
- 238000011084 recovery Methods 0.000 claims 1
- 239000002244 precipitate Substances 0.000 description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 229910021653 sulphate ion Inorganic materials 0.000 description 2
- ADFXKUOMJKEIND-UHFFFAOYSA-N 1,3-dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 1
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229910017974 NH40H Inorganic materials 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- QZIQJVCYUQZDIR-UHFFFAOYSA-N mechlorethamine hydrochloride Chemical compound Cl.ClCCN(C)CCCl QZIQJVCYUQZDIR-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- VLTRZXGMWDSKGL-UHFFFAOYSA-M perchlorate Inorganic materials [O-]Cl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229940072172 tetracycline antibiotic Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
(54) IMPROVEMENTS IN OR RELATING TO
TETRACYCLINE DERIVATIVES
(71) We, PLIVA PHARMA
CEUTICAL AND CHEMICAL
WORKS, of Ive Lole Ribara 89, Zagreb,
Yugoslavia, a Yugoslav body corporate, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement::- The present invention relates to N2 - t butyl - lia - halo - 6 - demethyl - 6 deoxy - 6 - methylene - tetracyclines and to a process for the preparation thereof, which comprises dehydration of the carboxamido group of 1 lea - halo - 6 demethyl - 6 - deoxy - 6 - methylene - tetracyclines and then the addition of t-butanol to the 1 la - halo - 6 - demethyl 6 - deoxy - 6 - methylene - tetracycline nitrile thus obtained.It is well-known that dehydration of the carboxamido group of tetracyclines, by means of alkylsulphonic and arylsulphonic acid chlorides in the presence of pyridine, enables nitriles of tetracyclines, of 5 - hydroxy - tetracyclines and of 7 - chloro - tetracyclines, as well as nitriles of Sa,6- anhydro derivatives thereof, to be prepared; these preparations are disclosed in Patent Specifications 766 512 and 808 702.
The preparation of nitriles of tetracyclines, of 5- hydroxy - tetracyclines and of 7 - chloro - tetracyclines, as well as of the corresponding 6 - demethyl 6 - deoxy - 5a,l la - dehydro derivatives, by dehydration with disubstituted carbodiimides is also known, from Patent
Specification 905 448.
It is further known that N2-substituted derivatives of tetra.-cyclines, of 5 hydroxy - tetracyclines and of 7 - chloro tetracyclines, as well as the 5a,6-anhydro derivatives thereof, can be prepared from nitriles of tetracyclines by reaction in a mixture of strong acids, whereupon simultaneous dehydration in the C1a-C6 position takes place, because of their sensitivity to acidic media, due to the presence of the hydroxy group in the 6position of the tetracycline molecule, (see
Patent Specifications 800 699 and 808 702 and US Patent Specification 3 275 652).
It has now been found that N2 - t - butyl - ila - halo - 6 - demethyl - 6 deoxy - 6 - methylene - tetracyclines, of the following structural formula (I) (referred to below as N2 t - butyl -lIa - halo - 6 methylene - tetracyclines) can be prepared by dehydration of the carboxamido group of 1 la - halo - 6 - methylene - tetracyclines, formula (II), and subsequent addition of tbutanol to the 1 la - halo - 6 - methylene tetracycline - nitrile, formula (III), obtained according to the following reaction scheme::
r=H or OH
X=CI or Br The resultant N2 - t - butyl - 1 lea - halo - 6 - demethyl - 6 - deoxy - 6 - methylene tetracyclines can serve as intermediates in the preparation of various tetracycline antibiotics.
According to a preferred feature of the present invention, the dehydration of 1 la halo - 6 - methylene - tetracyclines (it), wherein R represents a hydrogen atom or a hydroxy group and X represents a chlorine or bromine atom, is carried out in an inert solvent with 2 to 3.5 moles of dicyclohexylcarbodiimide (referred to below as DCCI).
The inert solvent preferably is methanol, ethanol, i-propanol or n-butanol and the dehydration reaction is advantageously carried out for 3 to 5 hours at room temperature. During the reaction, dicyclohexylurea (referred to below as DCU) crystallizes from the reaction mixture, besides the desired 1 lea - halo - 6 - methylene - tetracycline - nitrile (III). The reaction mixture is rendered alkaline to pH 7 to 8, the remaining precipitate of DCU is filtered off, the filtrate is acidified to pH 2 to 3, e.g. with concentrated HCI, and lla- halo - 6 - methylene - tetracycline - nitrile (III) precipitates. The compound III has been identified by its IR spectrum by the intensive peak at 4.55 ,um which is characteristic for nitriles.
The addition of t-butanol on the nitrile (III) so obtained is preferably carried out by dissolving the nitrile (III) in a mixture of glacial acetic acid and t-butanol, cooling the reaction mixture and adding concentrated sulphuric acid. After stirring for 20 to 25 hours at reduced temperature (about 50C), the reaction solution is poured into a mixture of ice and water, neutralized with
NaOH (400/ wlw aqueous solution) and extracted with chloroform. After removing chloroform, the N2 - t - butyl - 1 lea - halo 6 - methylene - tetracycline (I) so obtained no longer showed the characteristic nitrile peak at 4.55 p.
Identification by means of the NMR spectrum of the product showed a strong singlet at 1.55 8, which is characteristic for t-butyl.
The invention is illustrated by the following Examples, wherein Examples 1 to 4 illustrate the preparation of tetracyclinenitriles of formula III and Examples 5 to 7 illustrate the preparation of tetracycline derivatives of formula I from intermediates of formula III.
Example 1 11 a-Chloro-6-methylene-5-hydroxy- tetracycline-nitrile
Ila - Chloro - 6 - methylene - 5 hydroxy - tetracycline - sulphate (1 g) was dissolved in methanQI (10 ml) and DCCI (1 g) was added to the clear solution. After stirring for 4 hours at room temperature, the resulting precipitate was filtered off, washed with acetone (2 ml) and lla - chloro - 6 methylene - 5 - hydroxy - tetracycline nitrile was precipitated by adding diethyl
ether to the filtrate. After stirring for 2
hours, the precipitate was filtered off and
washed with diethyl ether. Recrystallisation
from a 1:20 mixture of dimethyl formamide
and methanol gave a pure substance.
Analysis for C22H21N2O7C1: calc.:
C 57.57on H 4.18% N 6.12%
Cl 7.73%
found:
C 57.90% H 3.88% N 6.16%
Cl 7.52%
IR (KBr) 4.55 ,u UVA max (0.01 N HCl/CH3OH) 232, 281,
358 nm
NMR (CF3COOH) 85.71 (s) and 6.22 (s)
Example 2 11 a-Chloro-6-methylene-5-hydroxy- tetracycline-nitrile
lla - Chloro - 6 - methylene - 5
hydroxy - tetracycline - sulphate (1 g) was
dissolved in methanol (10 ml).To the clear
solution, DCCI (1 g) was added and the
mixture was stirred for 5 hours at room
temperature. NH40H (25% wlw aqueous
solution) was added dropwise so as to
achieve a pH of 7.5 to 8 in the reaction
mixture, the precipitate was separated by
filtration and washed with methanol. By
acidifying the filtrate with concentrated HC1, the precipitation of 1 lea - chloro - 6
methylene - 5 - hydroxy - tetracycline
nitrile began. Stirring was continued for a
further 4 hours, the resulting precipitate was
filtered off and washed with acidic
methanol. Recrystallisation of the
precipitate from a 1:20 mixture of dimethyl
formamide and methanol gave a substance
with the same elementary analysis and
absorption spectra as in Example 1.
Example 3 1 la-Chloro-6-methylene- tetracycline-nitrile 1 lea - Chloro - 6 - methylene
tetracycline - perchlorate (1 g) was
suspended in methanol (20 ml), DCCI (I g)
was added and the mixture was stirred at
room temperature for 4 hours. 1 lea Chloro - methylene - tetracycline - nitrile
was isolated as in Example 2.
Example 4 1 la-Bromo-6-methylene-5-hydroxy- tetracycline-nitrile
lla - Bromo - 6 - methylene - 5
hydroxy - tetracycline - sulphosalicylate (1 g) was dissolved in methanol (10 ml). To the
clear solution, DCCI (0.8 g) was added.
While stirring at room temperature, the
nitrile began to precipitate very quickly,
together with urea. After stirring for 4
hours, the precipitate was filtered off,
washed with methanol and recrystallized from a 1:20:10 mixture of dimethyl formamide, t-butanol and diethyl ether.
Example 5 N2-t-Butyl- 1 la-chloro-6-methylene- 5-hydroxy-tetracycline
Ila - Chloro - 6 - methylene - 5 hydroxy - tetracycline - nitrile (1 g) was dissoved in a mixture of glacial acetic acid (10 ml) and t-butanol (1 ml). The mixture was cooled to 50C and sulphuric acid (2 ml of 98 /n w/w aqueous solution) was added.
After 24 hours, the reaction mixture was added dropwise to 100 ml of a mixture of ice and water, the pH of the solution was brought to 4.5 by adding NaOH (40% w/w aqueous solution) under good stirring and cooling and the mixture was extracted with chloroform. The combined extracts were washed with water, dried over calcium chloride and then evaporated to dryness under reduced pressure. Recrystallisation from diethyl ether gave a pure substance.
Analysis for C26H29N2O8Cl calc.: C 58.60% H 5.50% N 5.26% Cl 6.66 / found:
C 58.79% H 5.48% N 5.50%
Cl 6.90%
IR (KBr) 5.73 , 3.37 UVA max. (0.01 N HCl/CH3OH) 236, 275,
358 nm
NMR (CF3COOH) #1.53 (s) b5.7 (s) and 6.15 (s)
Example 6
N2-t-Butyl-l la-bromo-6-methylene
5-hydroxy-tetracycline
lla - Bromo - 6 - methylene - 5 hydroxy - tetracycline - nitrile (1 g) was dissolved in a mixture of glacial acetic acid (10 ml) and t-butanol (1 ml), cooled to 50C and concentrated sulphuric acid was added.
After 24 hours, N2 - t - butyl - lla - bromo - 6 - methylene - 5 - hydroxy tetracycline was isolated from the reaction solution as described in Example 5.
IR 5.73 u 3.37 p UVA max. (0.01 N HCl/CH3OH) 236, 276,
358 nm
NMR (CF3COOH) 81.53 (s) 85.7 (s) and
6.15 (s)
Example 7 N2-t-Butyl-l la-chloro-6-methylene- tetracycline 1 lea - Chloro - 6 - methylene - tetra cycline - nitrile (1 g) was dissolved in a mixture of glacial acetic acid (10 ml) and tbutanol (1 ml), cooled to 5"C and concentrated sulphuric acid (2 ml) was added. After 24 hours, N2 - t - butyl - 6 methylene - tetracycline was isolated from the reaction solution as described in
Example 5.
WHAT WE CLAIM IS:
1. N2 - t - Butyl - lla - halo - 6 demethyl - 6 - deoxy - 6 - methylene - tetracyclines of the general formula:
wherein R represents a hydrogen atom or a hydroxy group and X represents a chlorine or bromirie atom.
2. A process for the preparation of N2 t - butyl - ila - halo - 6 - demethyl - 6 deoxy - 6 - methylene - tetracyclines of the general formula I, which comprises subjecting 1 la - halo - 6 - demethyl - 6 deoxy - 6 - methylene - tetracycline of the general formula:
wherein R and X have the meanings defined above, to dehydration of the carboxamido group to obtain the corresponding lla- halo - 6 - demethyl - 6 - deoxy - 6methylene - tetracycline - nitrile of the general formula:
and then adding t-butanol to the nitrile so obtained.
3. A process as claimed in claim 2, wherein the dehydration of the carboxamido group is carried out in an inert solvent with 2 to 3.5 moles of dicyclohexylcarbodiimide.
4. A process as claimed in claim 3, wherein the solvent is methanol, ethanol, i- propanol or n-butanol.
5. A process as claimed in claim 3 or 4, wherein the dehydration reaction is carried out at room temperature for 3 to 5 hours.
6. A process as claimed in any of claims 3 to 5, wherein the 1 lea - halo - 6 - dimethyl 6 - deoxy - 6 - methylene - tetracycline nitrile is precipitated by rendering the reaction mixture alkaline to pH 7 to 8, filtering and acidifying the filtrate to pH 2 to 3.
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (13)
- **WARNING** start of CLMS field may overlap end of DESC **.from a 1:20:10 mixture of dimethyl formamide, t-butanol and diethyl ether.Example 5 N2-t-Butyl- 1 la-chloro-6-methylene-5-hydroxy-tetracycline Ila - Chloro - 6 - methylene - 5 hydroxy - tetracycline - nitrile (1 g) was dissoved in a mixture of glacial acetic acid (10 ml) and t-butanol (1 ml). The mixture was cooled to 50C and sulphuric acid (2 ml of 98 /n w/w aqueous solution) was added.After 24 hours, the reaction mixture was added dropwise to 100 ml of a mixture of ice and water, the pH of the solution was brought to 4.5 by adding NaOH (40% w/w aqueous solution) under good stirring and cooling and the mixture was extracted with chloroform. The combined extracts were washed with water, dried over calcium chloride and then evaporated to dryness under reduced pressure. Recrystallisation from diethyl ether gave a pure substance.Analysis for C26H29N2O8Cl calc.: C 58.60% H 5.50% N 5.26% Cl 6.66 / found: C 58.79% H 5.48% N 5.50% Cl 6.90% IR (KBr) 5.73 , 3.37 UVA max. (0.01 N HCl/CH3OH) 236, 275, 358 nm NMR (CF3COOH) #1.53 (s) b5.7 (s) and 6.15 (s) Example 6 N2-t-Butyl-l la-bromo-6-methylene5-hydroxy-tetracycline lla - Bromo - 6 - methylene - 5 hydroxy - tetracycline - nitrile (1 g) was dissolved in a mixture of glacial acetic acid (10 ml) and t-butanol (1 ml), cooled to 50C and concentrated sulphuric acid was added.After 24 hours, N2 - t - butyl - lla - bromo - 6 - methylene - 5 - hydroxy tetracycline was isolated from the reaction solution as described in Example 5.IR 5.73 u 3.37 p UVA max. (0.01 N HCl/CH3OH) 236, 276, 358 nm NMR (CF3COOH) 81.53 (s) 85.7 (s) and 6.15 (s) Example 7 N2-t-Butyl-l la-chloro-6-methylene- tetracycline 1 lea - Chloro - 6 - methylene - tetra cycline - nitrile (1 g) was dissolved in a mixture of glacial acetic acid (10 ml) and tbutanol (1 ml), cooled to 5"C and concentrated sulphuric acid (2 ml) was added. After 24 hours, N2 - t - butyl - 6 methylene - tetracycline was isolated from the reaction solution as described in Example 5.WHAT WE CLAIM IS: 1. N2 - t - Butyl - lla - halo - 6 demethyl - 6 - deoxy - 6 - methylene - tetracyclines of the general formula:wherein R represents a hydrogen atom or a hydroxy group and X represents a chlorine or bromirie atom.
- 2. A process for the preparation of N2 t - butyl - ila - halo - 6 - demethyl - 6 deoxy - 6 - methylene - tetracyclines of the general formula I, which comprises subjecting 1 la - halo - 6 - demethyl - 6 deoxy - 6 - methylene - tetracycline of the general formula:wherein R and X have the meanings defined above, to dehydration of the carboxamido group to obtain the corresponding lla- halo - 6 - demethyl - 6 - deoxy - 6methylene - tetracycline - nitrile of the general formula:and then adding t-butanol to the nitrile so obtained.
- 3. A process as claimed in claim 2, wherein the dehydration of the carboxamido group is carried out in an inert solvent with 2 to 3.5 moles of dicyclohexylcarbodiimide.
- 4. A process as claimed in claim 3, wherein the solvent is methanol, ethanol, i- propanol or n-butanol.
- 5. A process as claimed in claim 3 or 4, wherein the dehydration reaction is carried out at room temperature for 3 to 5 hours.
- 6. A process as claimed in any of claims 3 to 5, wherein the 1 lea - halo - 6 - dimethyl 6 - deoxy - 6 - methylene - tetracycline nitrile is precipitated by rendering the reaction mixture alkaline to pH 7 to 8, filtering and acidifying the filtrate to pH 2 to 3.
- 7. A process as claimed in any of claims 2to 6, wherein the nitrile III is dissolved in a mixture of glacial acetic acid and t-butanol, the reaction solution is cooled and concentrated sulphuric acid is added.
- 8. A process as claimed in claim 7, wherein recovery of the product I includes stirring the reaction solution for 20 to 25 hours at 5 C, pouring it into a mixture of ice and water, neutralizing with 40% wIw NaOH aqueous solution and extracting with chloroform.
- 9. A process as claimed in claim 8, wherein the product I is isolated by evaporation of the chloroform extract under reduced pressure.
- 10. A process for the preparation of N I - butyl - lla - halo - 6 - demethyl - 6 - deoxy - 6- methylene tetracyclines as claimed in claim 2, substantially as described with reference to the foregoing Examples.
- 11. N2 - t - Butyl - Ila - chloro - 6 demethyl - 6 deoxy - 6 - methylene - 5 - hydroxy - tetracycline, when prepared according to Example 5.
- 12. N2 - t Butyl - lla - bromo - 6 demethyl -6 - deoxy -6 - methylene - 5 hydroxy - tetracycline, when prepared according to Example 6.
- 13. N2 t- Butyl- lla - chloro - 6 demethyl - 6 - deoxy - 6 - methylene - tetracyline, when prepared according to Example 7.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| YU92277A YU40295B (en) | 1977-04-07 | 1977-04-07 | Process for preparing n2-tert.butyl-11a-halo-6-demethyl-6-deoxy-6-methylene tetracycline |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1571765A true GB1571765A (en) | 1980-07-16 |
Family
ID=25552009
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB1342878A Expired GB1571765A (en) | 1977-04-07 | 1978-04-06 | Tetracycline derivatives |
Country Status (3)
| Country | Link |
|---|---|
| DE (1) | DE2814974C2 (en) |
| GB (1) | GB1571765A (en) |
| YU (1) | YU40295B (en) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU3105801A (en) | 2000-01-24 | 2001-07-31 | Trustees Of Tufts College | Tetracycline compounds for treatment of cryptosporidium parvum related disorders |
| CA2457234A1 (en) | 2001-03-14 | 2002-09-19 | Mark L. Nelson | Substituted tetracycline compounds as antifungal agents |
| JP2005504722A (en) | 2001-03-14 | 2005-02-17 | パラテック ファーマシューティカルズ インコーポレイテッド | Substituted tetracycline compounds as synergistic antifungal agents |
| DE60235083D1 (en) | 2001-04-24 | 2010-03-04 | Paratek Pharm Innc | SUBSTITUTED TETRACYCLIN COMPOUNDS FOR THE TREATMENT OF MALARIA |
| US8088820B2 (en) | 2001-04-24 | 2012-01-03 | Paratek Pharmaceuticals, Inc. | Substituted tetracycline compounds for the treatment of malaria |
| AU2003287218C1 (en) | 2002-10-24 | 2010-07-15 | Paratek Pharmaceuticals, Inc. | Substituted tetracycline compounds for the treatment of malaria |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB800699A (en) * | 1955-05-09 | 1958-09-03 | Pfizer & Co C | Mono- and di-alkyl anhydrotetracyclines |
| DE1091564B (en) * | 1959-08-27 | 1960-10-27 | Hoechst Ag | Process for the preparation of nitriles of the tetracyclines |
-
1977
- 1977-04-07 YU YU92277A patent/YU40295B/en unknown
-
1978
- 1978-04-06 GB GB1342878A patent/GB1571765A/en not_active Expired
- 1978-04-06 DE DE19782814974 patent/DE2814974C2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| DE2814974A1 (en) | 1978-10-19 |
| YU92277A (en) | 1982-06-30 |
| DE2814974C2 (en) | 1984-06-14 |
| YU40295B (en) | 1985-12-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |