FI59395B - FRAMSTAELLNING AV ALFA-6-DEOXI-5-HYDROXITETRACYKLIN - Google Patents
FRAMSTAELLNING AV ALFA-6-DEOXI-5-HYDROXITETRACYKLIN Download PDFInfo
- Publication number
- FI59395B FI59395B FI753459A FI753459A FI59395B FI 59395 B FI59395 B FI 59395B FI 753459 A FI753459 A FI 753459A FI 753459 A FI753459 A FI 753459A FI 59395 B FI59395 B FI 59395B
- Authority
- FI
- Finland
- Prior art keywords
- rhodium
- deoxy
- hydroxytetracycline
- formula
- hydrogenation
- Prior art date
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- 238000005984 hydrogenation reaction Methods 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 239000010948 rhodium Substances 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000004098 Tetracycline Substances 0.000 claims description 6
- 229910052703 rhodium Inorganic materials 0.000 claims description 6
- 229960002180 tetracycline Drugs 0.000 claims description 6
- 229930101283 tetracycline Natural products 0.000 claims description 6
- 235000019364 tetracycline Nutrition 0.000 claims description 6
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 5
- 150000003522 tetracyclines Chemical class 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- 239000000203 mixture Substances 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- -1 rhodium (II) compound Chemical class 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 5
- 150000003284 rhodium compounds Chemical class 0.000 description 5
- ITDJKCJYYAQMRO-UHFFFAOYSA-L rhodium(2+);diacetate Chemical compound [Rh+2].CC([O-])=O.CC([O-])=O ITDJKCJYYAQMRO-UHFFFAOYSA-L 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 239000012442 inert solvent Substances 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- HYNAWOZNFYDQFQ-UHFFFAOYSA-K O.[Rh](O)(O)O Chemical compound O.[Rh](O)(O)O HYNAWOZNFYDQFQ-UHFFFAOYSA-K 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 229910052770 Uranium Inorganic materials 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- FQJSHYJMMZNGBA-UHFFFAOYSA-N rhodium(2+);triphenylphosphane Chemical compound [Rh+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 FQJSHYJMMZNGBA-UHFFFAOYSA-N 0.000 description 2
- BDDWSAASCFBVBK-UHFFFAOYSA-N rhodium;triphenylphosphane Chemical compound [Rh].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 BDDWSAASCFBVBK-UHFFFAOYSA-N 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 238000011916 stereoselective reduction Methods 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- WXHLLJAMBQLULT-UHFFFAOYSA-N 2-[[6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-yl]amino]-n-(2-methyl-6-sulfanylphenyl)-1,3-thiazole-5-carboxamide;hydrate Chemical compound O.C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1S WXHLLJAMBQLULT-UHFFFAOYSA-N 0.000 description 1
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000010531 catalytic reduction reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N diethylene glycol monoethyl ether Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 229910000040 hydrogen fluoride Inorganic materials 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- DGEYTDCFMQMLTH-UHFFFAOYSA-N methanol;propan-2-ol Chemical compound OC.CC(C)O DGEYTDCFMQMLTH-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- VUPQHSHTKBZVML-UHFFFAOYSA-J rhodium(3+);tetraacetate Chemical compound [Rh+3].[Rh+3].CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O VUPQHSHTKBZVML-UHFFFAOYSA-J 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical class OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 150000003511 tertiary amides Chemical class 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000003799 water insoluble solvent Substances 0.000 description 1
Classifications
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/22—Organic complexes
- B01J31/2204—Organic complexes the ligands containing oxygen or sulfur as complexing atoms
- B01J31/2208—Oxygen, e.g. acetylacetonates
- B01J31/2226—Anionic ligands, i.e. the overall ligand carries at least one formal negative charge
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/16—Catalysts comprising hydrides, coordination complexes or organic compounds containing coordination complexes
- B01J31/24—Phosphines, i.e. phosphorus bonded to only carbon atoms, or to both carbon and hydrogen atoms, including e.g. sp2-hybridised phosphorus compounds such as phosphabenzene, phosphole or anionic phospholide ligands
- B01J31/2404—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0073—Rhodium compounds
- C07F15/008—Rhodium compounds without a metal-carbon linkage
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5045—Complexes or chelates of phosphines with metallic compounds or metals
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F41—WEAPONS
- F41A—FUNCTIONAL FEATURES OR DETAILS COMMON TO BOTH SMALLARMS AND ORDNANCE, e.g. CANNONS; MOUNTINGS FOR SMALLARMS OR ORDNANCE
- F41A9/00—Feeding or loading of ammunition; Magazines; Guiding means for the extracting of cartridges
- F41A9/01—Feeding of unbelted ammunition
- F41A9/24—Feeding of unbelted ammunition using a movable magazine or clip as feeding element
- F41A9/26—Feeding of unbelted ammunition using a movable magazine or clip as feeding element using a revolving drum magazine
- F41A9/27—Feeding of unbelted ammunition using a movable magazine or clip as feeding element using a revolving drum magazine in revolver-type guns
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F41—WEAPONS
- F41A—FUNCTIONAL FEATURES OR DETAILS COMMON TO BOTH SMALLARMS AND ORDNANCE, e.g. CANNONS; MOUNTINGS FOR SMALLARMS OR ORDNANCE
- F41A9/00—Feeding or loading of ammunition; Magazines; Guiding means for the extracting of cartridges
- F41A9/29—Feeding of belted ammunition
- F41A9/30—Sprocket-type belt transporters
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2231/00—Catalytic reactions performed with catalysts classified in B01J31/00
- B01J2231/60—Reduction reactions, e.g. hydrogenation
- B01J2231/64—Reductions in general of organic substrates, e.g. hydride reductions or hydrogenations
- B01J2231/641—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes
- B01J2231/645—Hydrogenation of organic substrates, i.e. H2 or H-transfer hydrogenations, e.g. Fischer-Tropsch processes of C=C or C-C triple bonds
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2531/00—Additional information regarding catalytic systems classified in B01J31/00
- B01J2531/80—Complexes comprising metals of Group VIII as the central metal
- B01J2531/82—Metals of the platinum group
- B01J2531/822—Rhodium
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Inorganic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Catalysts (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Description
ir-^1 -.1 r_, .... KUULUTUSJULKAISU „ „ J&Tjf 11 UTLÄCGNINOSSKRIFT 59395 C (4S) Γαtentti sy'-innetty 10 03 1931 k MMTi Patent raeddelat V ’ ^ (SI) Ky.lk.3/lnt.C«.3 C 07 C 103/19 SUOM I — FI N LAN D (21) EwwttBwhwwm — P«»nttn»ekiWm 753^59 mm»**»-»*·***. 09.12.75 'ΓΙ' (23) Alkupllvl—GIMfh«t*dag 09-12-75 (41) Tullut lulkiMksI — SIMt offmdlg 20.06-76 PUMM-μ rrtbUrihdlltu. (44) ΝΚΜΗρ» μ ,..ir- ^ 1 -.1 r_, .... ADVERTISEMENT „„ J & Tjf 11 UTLÄCGNINOSSKRIFT 59395 C (4S) Γαtentti sy'-innetty 10 03 1931 k MMTi Patent raeddelat V '^ (SI) Ky.lk.3 / lnt. C «.3 C 07 C 103/19 ENGLISH I - FI N LAN D (21) EwwttBwhwwm - P« »nttn» ekiWm 753 ^ 59 mm »**» - »* · ***. 09.12.75 'ΓΙ' (23) Alkupllvl — GIMfh «t * dag 09-12-75 (41) Tullut lulkiMksI - SIMt offmdlg 20.06-76 PUMM-μ rrtbUrihdlltu. (44) ΝΚΜΗρ »μ, ..
Patent- och reglstwetyreletn ' AimMcm uthgd och utl.*krift*n puMtcand 30.04. Ö1 (32)(33)(31) ryydMty «««Xkwt—tagird prtoriut 19-12-7^ USA(US) 53UU52 (71) Pfizer Inc., 235 East U2nd Street, New York, N.Y., USA(US) (72) Herman Paubl, Mystic, Connecticut, USA(US) (7**) 0y Roister Ab (5^) n(J-6-deoksi-5 -hydroksitetrasykliinin valmistus - Framstalining av °<s-6-deoxi-5-hydroxitetracyklinPatent- and Reglstwetyreletn 'AimMcm uthgd och utl. * Krift * n puMtcand 30.04. Ö1 (32) (33) (31) ryydMty «« «Xkwt — tagird prtoriut 19-12-7 ^ USA (US) 53UU52 (71) Pfizer Inc., 235 East U2nd Street, New York, NY, USA (US) (72) Herman Paubl, Mystic, Connecticut, USA (7 **) 0y Preparation of Roister Ab (5 ^) n (J-6-deoxy-5-hydroxytetracycline - Framstalining av ° <s-6-deoxy-5 -hydroxitetracyklin
Keksinnön kohteena on menetelmä kaavan ch3 oh n(ch3)2The invention relates to a process of formula ch3 oh n (ch3) 2
-OH-OH
C0NH2 OH 0 OH 0 mukaisen o^-6-deoksi-5~hydroksitetrasykliinin tai sen happoadditiosuolan valmistamiseksi katalyyttisesti hydraamalla.For the catalytic hydrogenation of O, N-6-deoxy-5-hydroxytetracycline or an acid addition salt thereof according to CONH 2 OH 0 OH 0.
US-patentissa 3 200 11*9 esitetään c<-6-deoksitetrasykliinijohdannaisten valmistus menetelmällä, jossa hydrataan määrättyjä 6-deoksi-6-demetyyli-6-metyleenitetrasykliinejä käyttäen mukana katalyyttisiä määriä jalometallikataly- 2 59395 saattoria, kuten rodiumia tai palladiumia. Menetelmässä saadaan sekä yS-6-deoksi-tetrasykliinejä että <?<-6-deoksitetrasykliinejä. Eräänä tämän keksinnön päätarkoituksena on parantaa tätä menetelmää siten, että saadaan korkeampi c/.-iso-meerin ja y6-isomeerin suhde.U.S. Patent 3,200 11 * 9 discloses the preparation of α-β-deoxytetracycline derivatives by a process in which certain 6-deoxy-6-demethyl-6-methylenetetracyclines are hydrogenated using catalytic amounts of a noble metal catalyst such as rhodium or palladium. Both γS-6-deoxytetracyclines and β-deoxytetracyclines are obtained in the process. It is a main object of the present invention to improve this process by obtaining a higher ratio of the cis-isomer to the γ6-isomer.
Nyt on keksitty, että korkeampi p<-isomeerin ja y^-isomeerin suhde voidaan saada hydraamalla reaktioinertissä liuottimessa seos, jossa on 6-deoksi-6-demetyyli-6-metyleeni-5-hydroksitetrasykliiniyhdistettä ja määrättyä liukoista rodium(II)-yhdistettä. Tällainen liukoinen rodium(II)-yhdiste on dikarboksi-laatti(trifenyylifösfiini)rodituii(ll).It has now been found that a higher ratio of the β-isomer to the γ-isomer can be obtained by hydrogenating in a reaction-inert solvent a mixture of a 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline compound and a certain soluble rhodium (II) compound. Such a soluble rhodium (II) compound is dicarboxylate (triphenylphosphine) rhodium (II).
DE-hakemusjulkaisussa 2 308 227 on esitetty laajalti liukoisten rodium-yhdisteiden käyttöä 6-deoksi-6-demetyyli-6-metyleenitetrasykliinien stereo-selektiiviseen pelkistykseen. Tässä DE-hakemusjulkaisussa on kuitenkin esimerkkejä pelkästään rodium(l)-yhdisteiden käytöstä. Hui et ai. Inorganic Chemistry, 12 (1973) 757 ja Journal of the Chemical Society (Lontoo), osa D, 1195 (1970) esittävät, että rodium(ll)diasetaatti on tehokas hydrauskatalyytti. Rodium(II)di-asetaatin käyttö ei kuitenkaan keksinnön mukaisessa menetelmässä johda edulliseen oi- ja ^-yhdisteen suhteeseen: muodostuu suunnilleen yhtä suuret määrät oi- ja β-isomeerejä. Trifenyylifosfiinin ligandi on olennainen edellytys stereoselek-tiiviseen pelkistykseen. Vaikka Legzdins et ai., Journal of the Chemical Society (Lontoo), osa D, 825 (1969)» ovat esittäneet rodiumdiasetaattia käytettäväksi hydrauskatalyyttinä trifenyylifosfiinin läsnäollessa, heidän kokeensa suoritettiin erittäin vahvan hapon läsnäollessa. Keksinnön mukainen menetelmä suoritetaan neutraaleissa olosuhteissa tai heikosti happamilla tetrasykliinin happoadditio-suoloilla.DE-A-2 308 227 discloses the use of widely soluble rhodium compounds for the stereoselective reduction of 6-deoxy-6-demethyl-6-methylenetetracyclines. However, there are examples in this DE application of the use of rhodium (I) compounds alone. Hui et al. Inorganic Chemistry, 12 (1973) 757 and Journal of the Chemical Society (London), Part D, 1195 (1970) disclose that rhodium (II) diacetate is an effective hydrogenation catalyst. However, the use of rhodium (II) diacetate in the process according to the invention does not lead to a preferred ratio of oi- and β-compounds: approximately equal amounts of oi- and β-isomers are formed. Triphenylphosphine ligand is an essential condition for stereoselective reduction. Although Legzdins et al., Journal of the Chemical Society (London), Part D, 825 (1969), have proposed rhodium diacetate for use as a hydrogenation catalyst in the presence of triphenylphosphine, their experiments were performed in the presence of a very strong acid. The process according to the invention is carried out under neutral conditions or with weakly acidic acid addition salts of tetracycline.
Esillä oleva keksintö perustuu havaintoon, että hydrattaessa reaktioinertissä liuottimessa 6-deoksi-6-demetyyli-6-metyleeni-5~hydroksitetrasykliinin ja määrätyn rodiumyhdisteen seosta eksosyklinen metyleeniryhmä hydrautuu, ja hydraus tapahtuu stereoselektiivisesti suosien c<-isomeerin muodostumista ^-isomeerin kustannuksella vähintään suhteessa 9:1- Keksinnön kohteena on siten hydrausmenetelmä, jolle on tunnusomaista, että kaavan ch2 oh n(ch3)2The present invention is based on the finding that upon hydrogenation in a reaction-inert solvent of a mixture of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline and a certain rhodium compound, the exocyclic methylene group is hydrogenated and the hydrogenation occurs stereoselectively favoring the formation of the isomer at least The invention thus relates to a hydrogenation process which is characterized in that the formula ch2 oh n (ch3) 2
i)—0Hi) -0H
I .OHI .OH
— conh2 OH 0 0 3 59395 mukainen 6-deoksi-6-demetyyli-6-metyleeni-5-hydroksitetrasykliini, jonka kaavassa Z on- 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline of the formula Zh according to conh2 OH 0 0 3 59395
I II I
irr tai o =irr or o =
OHOH
tai sen happoadditiosuola hydrataan lämpötilassa U0~70°C hydrauspaineen ollessa noin 5 atm kun mukana on kaavanor an acid addition salt thereof is hydrogenated at a temperature of U0 ~ 70 ° C with a hydrogenation pressure of about 5 atm in the presence of the formula
Rh(OCOR)2(P/C6H573) mukaista rodiumkatalyyttiä, jonka kaavassa R on 1-3 hiiliatomia sisältävä alkyyli, ja jonka määrä on 1-10 mooli-# tetrasykliinin määrästä laskettuna.A rhodium catalyst according to Rh (OCOR) 2 (P / C6H573), in which R is alkyl having 1 to 3 carbon atoms, in an amount of 1 to 10 mol%, based on the amount of tetracycline.
Erityisen edullinen katalyytti on sellainen rodiumyhdiste, jonka kaavassa R on metyyli.A particularly preferred catalyst is a rhodium compound of the formula R is methyl.
Esillä olevan keksinnön lähtöaineina käytetään seuraavia yhdisteitä ch2 oh n(ch3)2The following compounds ch2 oh n (ch3) 2 are used as starting materials of the present invention
—0H-0H
^ -C0NH2 OH 0 OH o CH2 OH 1j(CH3)2^ -CONH2 OH 0 OH o CH2 OH 1j (CH3) 2
v —0Hv —0H
OH 0 0 0 ja niiden happoadditiosuoloja.OH 0 0 0 and their acid addition salts.
Näiden lähtöaineiden valmistus on täysin esitetty ja kuvattu US-patentissa 3 200 1h9- Yleisesti esittäen valmistusmenetelmä käsittää sopivan tetrasykliini-yhdisteen 11a-kloori-6,12-hemiketaalin käsittelyn vahvalla dehydratoivalla hapolla, kuten rikki-, trifluorietikka-, polyfosfori-, perkloori- tai fluorivety- 11 59395 hapolla tms. Näistä fluorivety on edullisin. Parhaat olosuhteet voidaan helposti määrittää tavanomaisilla kokeilla. Yleensä valittu 11a-klooriketaali vain lisätään valittuun happoon ja reaktion annetaan tapahtua sopivimmin lämpötila-alueella 0~50°C useamman tunnin ajan. Reaktion päätyttyä tuote otetaan talteen sopivalla tavalla, esimerkiksi käytettäessä haihtuvaa happoa haihduttamalla tämä, jolloin saadaan haihdutusjäännös, ja muissa tapauksissa standardimenetelmin, kuten sekoittamalla reaktioseosta liuottimen kanssa, johon tuote ei liukene, esimerkiksi dietyylieetterin kanssa, jolloin tuote saostuu. Nämä 6-metyleeniyhdisteet voidaan muuttaa happoadditiosuoloiksi tai polyvalenssisiksi metallikomplekseiksi tavanomaisin menetelmin ennen hydrausta.The preparation of these starting materials is fully disclosed and described in U.S. Patent 3,200-1h. hydrofluoric acid or the like. Hydrogen fluoride is most preferred. The best conditions can be easily determined by conventional experiments. Generally, the selected 11α-chloroketal is only added to the selected acid and the reaction is preferably allowed to proceed at a temperature in the range of 0-50 ° C for several hours. Upon completion of the reaction, the product is recovered in a suitable manner, for example by using a volatile acid by evaporation to give an evaporation residue, and in other cases by standard methods such as stirring the reaction mixture with an insoluble solvent, for example diethyl ether. These 6-methylene compounds can be converted to acid addition salts or polyvalent metal complexes by conventional methods prior to hydrogenation.
Kun haluttu lähtöaine on 11a-dekloori-6-deoksi-6-demetyyli-6-metyleeni-tetrasykliini, niin 11a-deklooraus voidaan suorittaa joko kemiallisella tai katalyyttisellä pelkistyksellä käyttäen alalla hyvin tunnettuja menetelmiä. US-patentin 3 200 1^9 esimerkissä XXXVII on kuvattu 11a-kloori-6-deoksi-6-demetyyli-6-metyleenitetrasykliinihydrokloridin hydrauspelkistys vastaavaksi 11a-deklooriyhdisteeksi.When the desired starting material is 11α-dechloro-6-deoxy-6-demethyl-6-methylene tetracycline, the 11α-dechlorination can be performed by either chemical or catalytic reduction using methods well known in the art. Example XXXVII of U.S. Patent 3,200-1,9 describes the hydrogen reduction of 11α-chloro-6-deoxy-6-demethyl-6-methylenetetracycline hydrochloride to the corresponding 11α-dechloro compound.
Kaavanformula
Rh(0C0R)2QRh (0C0R) 2Q
mukaiset rodiumyhdisteet ovat joko ennestään tunnettuja tai ennestään tunnettujen yhdisteiden yksinkertaisia analogeja tai homologeja, ja niitä voidaan valmistaa Stephenson'in et ai,, Journal of the Chemical Society (Lontoo), 3632 (1965), esittämillä menetelmillä. Näiden valmistusmenetelmien mukaan rodiumkarboksilaat-teja valmistetaan keittämällä rodiumhydroksidihydraattia palauttaen esimerkiksi ylimäärässä etikka- tai propionihappoa ja etanolia. Keltaiset liuokset muuttuvat vähitellen meripihkanvärisiksi ja sitten vihreiksi. Saadut liuokset jäähdytetään, ja saostuvat tummanvihreät jauheet suodatetaan ja kiteytetään uudelleen metano-lista tai vedestä. Näiden tuotteiden on havaittu olevan pysyviä aina lämpötiloihin 2U0°C asti. Lopullinen katalyyttikompleksi valmistetaan lisäämällä trifenyylifosfiinia ja dietyylieetteriä rodiumkarhoksilaatin kylmään etanoli-liuokseen.The rhodium compounds according to the invention are either known or simple analogs or homologues of the known compounds and can be prepared by the methods described by Stephenson et al., Journal of the Chemical Society (London), 3632 (1965). According to these methods of preparation, rhodium carboxylates are prepared by boiling rhodium hydroxide hydrate, recovering, for example, an excess of acetic or propionic acid and ethanol. The yellow solutions gradually turn amber and then green. The resulting solutions are cooled and the precipitated dark green powders are filtered and recrystallized from methanol or water. These products have been found to be stable up to temperatures up to 2U0 ° C. The final catalyst complex is prepared by adding triphenylphosphine and diethyl ether to a cold ethanol solution of rhodium carboxylate.
Sopivia reaktioinerttejä liuottimia käytettäviksi esillä olevassa keksinnössä ovat sellaiset, jotka pystyvät olennaisesti liuottamaan lähtöaineet tai tuotteen. Esimerkkejä tällaisista liuottimista ovat mm. eetterit, kuten dietyyli-eetteri, tetrahydrofuraani, dioksaani, 1,2-dimetoksietaani, alemmat alifaattiset ketonit, kuten asetoni ja metyylietyyliketoni, alhaisen molekyylipainon omaavat esterit, kuten etyyliasetaatti ja butyyliasetaatti, mono- ja polyhydriset alemmat 5 59395 alkoholit, kuten metanoli, etanoli, isopropanoli, etyleeniglykoli, propyleeni-glykoli ja dietyleeniglykoli, alemmat alkoksisubstituoidut alkanolit, kuten 2-metoksietanoli ja 2-(2-etoksietoksi)etanoli, alemmat alkaanihapot, kuten etikka-happo ja propionihappo, tertiääriset amidit, kuten Ν,Ν-dimetyyliformamidi , N,N-dimetyyliasetamidi ja N-metyylipyrrolidoni ja näiden seokset.Suitable reaction-inert solvents for use in the present invention are those capable of substantially dissolving the starting materials or product. Examples of such solvents are e.g. ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, lower aliphatic ketones such as acetone and methyl ethyl ketone, low molecular weight esters such as ethyl acetate and butyl acetate, mono- and polyhydric lower alcohols such as methanol, ethanol, such as methanol isopropanol, ethylene glycol, propylene glycol and diethylene glycol, lower alkoxy-substituted alkanols such as 2-methoxyethanol and 2- (2-ethoxyethoxy) ethanol, lower alkanoic acids such as acetic acid and propionic acid, tertiary amides such as Ν, N-dimethylacetamide and N-methylpyrrolidone and mixtures thereof.
Vetykaasun vieminen reaktioinerttiin liuottimeen, joka sisältää rodium-yhdisteen ja tetrasykliinin, suoritetaan yleensä suljetussa reaktioastiassa vety-atmosfäärissä tai vedyn ja inertin laimennuskaasun, kuten typen tai argonin seoksessa. Hydrauspaine on noin 5 atm.The introduction of hydrogen gas into a reaction-inert solvent containing a rhodium compound and a tetracycline is generally carried out in a sealed reaction vessel under a hydrogen atmosphere or in a mixture of hydrogen and an inert diluent gas such as nitrogen or argon. The hydrogenation pressure is about 5 atm.
Hydraus suoritetaan yleensä lämpötiloissa noin UO - noin 70°C. Käytettäessä edullisia lämpötila- ja paineolosuhteita hydraus vie aikaa tavallisesti joitakin tunteja, esimerkiksi noin 2 tunnista noin 10 tuntiin.The hydrogenation is generally carried out at temperatures of about UO to about 70 ° C. Using the preferred temperature and pressure conditions, the hydrogenation usually takes a few hours, for example from about 2 hours to about 10 hours.
Hydrattaessa lla-kloori 6-metyleeni-6-deoksi-6-demetyylitetrasykliini-lähtöaine tämän keksinnön menetelmällä lla-kloorienbetituentti poistuu.Upon hydrogenation of 11a-chloro, the 6-methylene-6-deoxy-6-demethyltetracycline starting material by the process of this invention removes the 11a-chloro betentifier.
Käytettävän katalyytin edullinen määrä on noin 1 - noin 10 mooli-% tetrasykliinin määrästä laskettuna.The preferred amount of catalyst to be used is from about 1 to about 10 mole percent based on the amount of tetracycline.
Esillä olevan keksinnön reaktiotuote voidaan eristää reaktioväliaineesta standardimenetelmin. Tuote voidaan esimerkiksi usein saada saostumaan lisäämällä ei-liuotinta, kuten heksaania tai vettä, tai lisäämällä määrättyjä aineita, jotka muodostavat liukenemattomia suoloja tuotteen kanssa. Vaihtoehtoisesti voidaan eristää raaka tuote haihduttamalla liuotin tai laimentamalla reaktioseos suurella ylimäärällä vettä ja sen jälkeen uuttamalla tuote veteen liukenemattomaan orgaaniseen liuottimeen ja lopuksi haihduttamalla veteen liukenematon liuotin.The reaction product of the present invention can be isolated from the reaction medium by standard methods. For example, the product can often be precipitated by the addition of a non-solvent such as hexane or water, or by the addition of certain substances that form insoluble salts with the product. Alternatively, the crude product can be isolated by evaporating the solvent or diluting the reaction mixture with a large excess of water and then extracting the product into a water-insoluble organic solvent and finally evaporating the water-insoluble solvent.
Katalyytin valmistus A. Rodium(II)asetaattidimeerin valmistusCatalyst preparation A. Preparation of rhodium (II) acetate dimer
Seosta, jossa oli 1,72 g rodiumhydroksidihydraattia /Rh(0H)^.H2Q7, 6 ml jääetikkaa ja 15 ml etanolia, kuumennettiin palauttaen 2k tuntia. Reaktioseos jäähdytettiin, haihtuvat ainekset poistettiin haihduttamalla tyhjössä, jolloin saatiin raakatuote, Raakatuote puhdistettiin liuottamalla se asetoniin, antamalla liuottimen hitaasti haihtua ja sitten suodattamalla saostunut kiinteä aine.A mixture of 1.72 g of rhodium hydroxide hydrate / Rh(0H) ^.H2Q7, 6 ml of glacial acetic acid and 15 ml of ethanol was heated under reflux for 2 hours. The reaction mixture was cooled, the volatiles removed by evaporation in vacuo to give the crude product. The crude product was purified by dissolving it in acetone, allowing the solvent to slowly evaporate and then filtering the precipitated solid.
B, Diasetato(trifenyylifosfiini)rodium(ll);n valmistusB, Preparation of diacetato (triphenylphosphine) rhodium (II);
Seos, jossa oli 110 mg rodium(H)asetaattidimeeriä ja 100 ml metanolia, jäähdytettiin 17°C:seen, ja seokseen lisättiin sekoittaen liuos, jossa oli 131 mg trifenyylifosfiinia 5 ml:ssa eetteriä. Sekoitusta jatkettiin huoneen lämpötilassa 2 tuntia, sitten sakka poistettiin suodattamalla. Saatiin 219 mg diasetato(trifenyylifosfiini)rodium(ll):ta, sp. 203-20U°C.A mixture of 110 mg of rhodium (H) acetate dimer and 100 ml of methanol was cooled to 17 ° C, and a stirred solution of 131 mg of triphenylphosphine in 5 ml of ether was added to the mixture. Stirring was continued at room temperature for 2 hours, then the precipitate was removed by filtration. 219 mg of diacetato (triphenylphosphine) rhodium (II) were obtained, m.p. 203-20U ° C.
6 5$ 39 56 5 $ 39 5
Vertailuesimerkki 6-deoksi-6-demetyyli-6-metyleeni-5-hydroksitetrasykliinin pelkistys käyttäen rodium(ll)diasetaattiaComparative Example Reduction of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline using rhodium (II) diacetate
Liuosta, jossa oli 2,0 g (1+,1β mmoolia) 6-deoksi-6-demetyyli-6-metyleeni-5-hydroksitetrasykliini-hydrokloridia ja 1+6 mg (5 mooli-?) rodium(lI)diasetaattia 30 ml:ssa kaasuttomaksi tehtyä metanolia, ravisteltiin vetyatmosfäärissä 65-70°C:ssa 5»25 tuntia. Vedyn paine reaktioastiassa oli 1+,56-1+,91 kg/cm^. Jäähdytetty reaktioastia avattiin, ja sen sisältö suodatettiin. Suodos tutkittiin korkeapainenestekromatografialla. Tämä osoitti, että liuos sisälsi o<-6-deoksi-5-hydroksitetrasykliiniä ja /0-6-deoksitetrasykliiniä suhteessa noin 2:3 yhdessä pienen määrän kanssa pelkistymätöntä lähtöainetta.A solution of 2.0 g (1 +, 1β mmol) of 6-deoxy-6-demethyl-6-methylene-5-hydroxytetracycline hydrochloride and 1 + 6 mg (5 mol) of rhodium (II) diacetate in 30 ml degassed methanol, was shaken under a hydrogen atmosphere at 65-70 ° C for 5-25 hours. The hydrogen pressure in the reaction vessel was 1 +, 56-1 +, 91 kg / cm 2. The cooled reaction vessel was opened and its contents filtered. The filtrate was examined by high pressure liquid chromatography. This indicated that the solution contained? -6-deoxy-5-hydroxytetracycline and? -6-deoxytetracycline in a ratio of about 2: 3 together with a small amount of unreduced starting material.
Seuraava esimerkki valaisee keksintöä.The following example illustrates the invention.
Esimerkki 6-metyleeni-6-demetyyli-6-deoksi-5-hydroksitetrasykliinin pelkistys käyttämällä diasetaatti(trifenyylifosfiini)rodium(II):taExample Reduction of 6-methylene-6-demethyl-6-deoxy-5-hydroxytetracycline using diacetate (triphenylphosphine) rhodium (II)
Liuosta, jossa oli 2,0 g (1+,18 mmoolia) 6-metyleeni-6-demetyyli-6~deoksi- 5-hydroksitetrasykliini-hydrokloridia ja 0,088 g (U,U mooli-?) diasetato(tri- fenyylifosfiini)rodium(ll):ta 30 ml:ssa kaasuvapaata metanolia, ravisteltiin ....... . - o vetyatmosfaanssa suljetussa astiassa 60-70 C:ssa 5,75 tuntia, Vedyn paine 2 reaktioastiassa oli 1+,63-1+,98 kg/cm , Sitten astia avattiin ja reaktioliuos suodatettiin. Suodos tutkittiin korkeapainenestekromatografiällä, joka osoitti, että se sisälsi haluttua o<-6-deoksi-5~hydroksitetrasykliiniä, jossa oli epäpuhtautena 2-3 ? sen C-6-epimeeriä.A solution of 2.0 g (1 +, 18 mmol) of 6-methylene-6-demethyl-6-deoxy-5-hydroxytetracycline hydrochloride and 0.088 g of (U, U molar) diacetato (triphenylphosphine) rhodium (II) in 30 ml of gas-free methanol, was shaken ........ - in a hydrogen atmosphere in a sealed vessel at 60-70 ° C for 5.75 hours, the hydrogen pressure in reaction vessel 2 was 1 +, 63-1 +, 98 kg / cm 3, The vessel was then opened and the reaction solution was filtered. The filtrate was examined by high performance liquid chromatography, which showed that it contained the desired o <-6-deoxy-5-hydroxytetracycline with an impurity of 2-3? its C-6 epimer.
Sitten suodokseen lisättiin sekoittaen 20 ml vettä ja 30 ml 10-?:ista sulfosalisyylihapon vesiliuosta. Sekoitusta jatkettiin yli yön, ja sitten sakka suodatettiin, jolloin saatiin 2,62 g (95 ?:n saanto) +^-6-deoksi-5-hydroksi-tetrasykliiniä sulfosalisylaattisuolana, UV-spektroskopialla osoitettiin tuotteen olevan 93-?risesti puhdasta.Then, 20 ml of water and 30 ml of a 10 .mu.l aqueous solution of sulfosalicylic acid were added to the filtrate with stirring. Stirring was continued overnight, and then the precipitate was filtered to give 2.62 g (95% yield) of +? - 6-deoxy-5-hydroxy-tetracycline as sulfosalicylate salt, UV spectroscopy showed the product to be 93% pure.
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