NO164241B - PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC 7- (DIMETHYLAMINOMETHYL) AMINO-9A METOXYMITOSAN. - Google Patents
PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC 7- (DIMETHYLAMINOMETHYL) AMINO-9A METOXYMITOSAN. Download PDFInfo
- Publication number
- NO164241B NO164241B NO890809A NO890809A NO164241B NO 164241 B NO164241 B NO 164241B NO 890809 A NO890809 A NO 890809A NO 890809 A NO890809 A NO 890809A NO 164241 B NO164241 B NO 164241B
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- Norway
- Prior art keywords
- amino
- methoxymitosane
- dimethylaminomethylene
- mitomycin
- preparation
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 5
- -1 DIMETHYLAMINOMETHYL Chemical class 0.000 title 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 11
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 3
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 229960004857 mitomycin Drugs 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 7
- HYFMSAFINFJTFH-UHFFFAOYSA-N Mitomycin-A Natural products O=C1C(OC)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)N2CC2NC21 HYFMSAFINFJTFH-UHFFFAOYSA-N 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- HYFMSAFINFJTFH-NGSRAFSJSA-N mitomycin A Chemical compound O=C1C(OC)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@]1(OC)N2C[C@@H]2N[C@@H]21 HYFMSAFINFJTFH-NGSRAFSJSA-N 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- 239000003480 eluent Substances 0.000 description 3
- 238000000855 fermentation Methods 0.000 description 3
- 230000004151 fermentation Effects 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- UZUUQCBCWDBYCG-UHFFFAOYSA-N Mitomycin B Natural products O=C1C(OC)=C(C)C(=O)C2=C1C(COC(N)=O)C1(O)N2CC2C1N2C UZUUQCBCWDBYCG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- UZUUQCBCWDBYCG-DQRAMIIBSA-N mitomycin B Chemical compound O=C1C(OC)=C(C)C(=O)C2=C1[C@H](COC(N)=O)[C@]1(O)N2C[C@H]2[C@@H]1N2C UZUUQCBCWDBYCG-DQRAMIIBSA-N 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000004566 IR spectroscopy Methods 0.000 description 1
- 229930192392 Mitomycin Natural products 0.000 description 1
- HRHKSTOGXBBQCB-UHFFFAOYSA-N Mitomycin E Natural products O=C1C(N)=C(C)C(=O)C2=C1C(COC(N)=O)C1(OC)C3N(C)C3CN12 HRHKSTOGXBBQCB-UHFFFAOYSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- ZSXGLVDWWRXATF-UHFFFAOYSA-N N,N-dimethylformamide dimethyl acetal Chemical compound COC(OC)N(C)C ZSXGLVDWWRXATF-UHFFFAOYSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- MGHPNCMVUAKAIE-UHFFFAOYSA-N diphenylmethanamine Chemical compound C=1C=CC=CC=1C(N)C1=CC=CC=C1 MGHPNCMVUAKAIE-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- HRHKSTOGXBBQCB-VFWICMBZSA-N methylmitomycin Chemical compound O=C1C(N)=C(C)C(=O)C2=C1[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N(C)[C@H]3CN12 HRHKSTOGXBBQCB-VFWICMBZSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 1
- 229950004406 porfiromycin Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
Description
Den foreliggende oppfinnelse vedrører en fremgangsmåte til fremstilling av krystallinsk 7-(dimetylaminometylen)amino-9a-metoksymitosan med formelen The present invention relates to a method for the production of crystalline 7-(dimethylaminomethylene)amino-9a-methoxymitosane with the formula
Denne er stabil selv ved temperaturer på opp til 100°C. This is stable even at temperatures of up to 100°C.
Mitomycin C er et antibiotikum, som fremstilles ved fermen- Mitomycin C is an antibiotic, which is produced by fermenta-
tering og som for tiden markedsføres under godkjennelse av US Food and Drug Administration for anvendelse ved behandling av dissimi- and which is currently marketed under approval by the US Food and Drug Administration for use in the treatment of dissimil-
nert adenocarcinoma i mage eller bukspyttkjertel i utprøvde kombi-nasjoner med andre godkjente kjemoterapeutiske midler, og som pal-liativ behandling når andre modaliteter har sviktet (MutamycirrH Physician's Desk Reference 38th Edition, 1984, p. 750). US-patentskrift 3.660.578 vedrører Mitomycin C og fremstillingen derav ved fermentering. nert adenocarcinoma of the stomach or pancreas in proven combinations with other approved chemotherapeutic agents, and as palliative treatment when other modalities have failed (Mutamycirrh Physician's Desk Reference 38th Edition, 1984, p. 750). US patent 3,660,578 relates to Mitomycin C and its preparation by fermentation.
Strukturene til Mitomycin A, B, C og porfiromycin ble først offentliggjort av J.S. Webb et al i J. Amer. Chem. Soc., Vol 84, The structures of Mitomycin A, B, C and Porfiromycin were first published by J.S. Webb et al in J. Amer. Chem. Soc., Vol 84,
1962, p. 3185-3187. En av de kjemiske omdanninger som ble benyttet ved strukturundersøkelsen for å klarlegge sammenhengen mellom mitomycin A og mitomycin C var omdannelsen av førstnevnte, 7,9a-dimetoksymitosan, ved omsetning med ammoniakk til sistnevnte, 1962, pp. 3185-3187. One of the chemical transformations used in the structural investigation to clarify the relationship between mitomycin A and mitomycin C was the transformation of the former, 7,9a-dimethoxymitosane, by reaction with ammonia into the latter,
7-amino-9a-metoksymitosan. Fortrengningen av 7-metoksygruppen i mitomycin A har vist seg å være en reaksjon av betydelig interesse i forbindelse med fremstilling av antitumoraktive derivater av mitomycin C. Hver av de nedenfor anførte artikler og patentskrifter vedrører omdanningen av mitomycin A til et 7-substituert aminomito-mycin C-derivat med antitumoraktivitet: Matsui et al "The Journal of Antibiotics", Vol XXI, 1968, p.189-198, 7-amino-9α-methoxymitosane. The displacement of the 7-methoxy group in mitomycin A has proven to be a reaction of considerable interest in connection with the production of antitumor active derivatives of mitomycin C. Each of the articles and patents listed below relates to the conversion of mitomycin A to a 7-substituted aminomitomycin C derivative with antitumor activity: Matsui et al "The Journal of Antibiotics", Vol XXI, 1968, p.189-198,
Kinoshita et al "J. Med. Chem", Vol 14, 1971, p.103-109, Iyengar et al "J. Med. Chem", Vol 24, 1981, p. 975-981, Iyengar, Sami, Remers og Bradner, Abstracts of Papers - Annual Meeting of The American Chemical Society, Las Vegas, Nevada, mars 1982, Abstract nr. MEDI 72, Kinoshita et al "J. Med. Chem", Vol 14, 1971, p.103-109, Iyengar et al "J. Med. Chem", Vol 24, 1981, p. 975-981, Iyengar, Sami, Remers and Bradner, Abstracts of Papers - Annual Meeting of The American Chemical Society, Las Vegas, Nevada, March 1982, Abstract No. MEDI 72,
Sasaki et al, Internat. J. Pharm. Vol. 15, 1983, p. 49. Sasaki et al., Internat. J. Pharm. Vol. 15, 1983, p. 49.
Følgende patentskrifter vedrører fremstilling av 7-substi-tuerte aminomitosanderivater ved omsetning av mitomycin A, mitomycin B eller et N^"a-substituert derivat derav med et primært eller sekundært amin: US-patentskrifter nr. 3.332.944, 3.420.846, 3.450.705, 3.514.452, 4.231.936, samt 4.268.676. The following patents relate to the preparation of 7-substituted aminomitosane derivatives by reacting mitomycin A, mitomycin B or an N^"a-substituted derivative thereof with a primary or secondary amine: US Patent Nos. 3,332,944, 3,420,846, 3,450 .705, 3,514,452, 4,231,936, as well as 4,268,676.
Mitomycin C derivater med en substituert aminogruppe i 7-stillingen har vært fremstilt ved direkte biosyntese, dvs. ved supplering av fermenteringsmedier med en rekke primære aminer og utførelse av konvensjonell mitomycinfermentering (CA. Claridge et al, Abst. of the Annual Meeting of Amer. Soc. for Microbiology, 1982, Abs. 028). Mitomycin C derivatives with a substituted amino group in the 7-position have been produced by direct biosynthesis, i.e. by supplementing fermentation media with a number of primary amines and performing conventional mitomycin fermentation (CA. Claridge et al, Abst. of the Annual Meeting of Amer. Soc. for Microbiology, 1982, Abs. 028).
Belgisk patentskrift 896.963 vedrører en gruppe monoguani-dino- eller mono- og bis-amidinoanaloger av mitomycin C, hvor enten 7-aminonitrogenatomet eller N^^-karbamoylnitrogenatomet i mitomycin C eller begge disse nitrogenatomer inngår som en del av en amidino-substituent, eller hvor 7-aminonitrogenatomet inngår som en del av en guanidinogruppe. En slik forbindelse fremstilt ifølge eksemplene 8 og 15 i patentskriftet er forbindelsen 7-(dimetylaminometylen)-amino-9a-metoksymitosan med følgende formel: Belgian patent document 896,963 relates to a group of monoguanidino or mono- and bis-amidino analogues of mitomycin C, where either the 7-amino nitrogen atom or the N^^-carbamoyl nitrogen atom in mitomycin C or both of these nitrogen atoms are included as part of an amidino substituent, or where the 7-aminonitrogen atom is included as part of a guanidino group. One such compound prepared according to examples 8 and 15 in the patent document is the compound 7-(dimethylaminomethylene)-amino-9a-methoxymitosane with the following formula:
Denne forbindelse som oppnås som et amorft fast stoff, har en høy aktivitet mot P-3 88 leukemi hos mus, en aktivitet som over-stiger aktiviteten av mitomycin C både med hensyn til maksimal virkning og milligramstyrke (forholdsmessige dosestørrelser ved ekvivalente virkninger). Forbindelsen er imidlertid generelt usta-bil ved 25-56°C. F,n krystallinsk form av 7-(dimetylaminometylen)-amino-9a-metoksymitosan har vist seg å være stabil selv ved temperaturer på opptil 100°C i seks dager eller mer. Denne krystallinske form gir et IR-spektrum som vist på den medfølgende tegning og har vesentlig større lagringsstabilitet enn amorft 7-(dimetylamino-. metylen)amino-9a-metoksymitosan. This compound, obtained as an amorphous solid, has a high activity against P-3 88 leukemia in mice, an activity that exceeds that of mitomycin C both in terms of maximal activity and milligram strength (proportional dose sizes at equivalent effects). However, the compound is generally unstable at 25-56°C. A crystalline form of 7-(dimethylaminomethylene)-amino-9a-methoxymitosane has been shown to be stable even at temperatures up to 100°C for six days or more. This crystalline form gives an IR spectrum as shown in the accompanying drawing and has significantly greater storage stability than amorphous 7-(dimethylamino-.methylene)amino-9a-methoxymitosane.
Amorft 7-(dimetylaminometylen)amino-9a-metoksymitosan fremstilles ved fremgangsmåten ifølge eksemplene 8 og 15 i ovennevnte belgiske patentskrift nr. 896.963. Disse fremgangsmåter er beskrevet nedenfor. Amorphous 7-(dimethylaminomethylene)amino-9a-methoxymitosane is prepared by the method according to examples 8 and 15 in the above-mentioned Belgian patent document no. 896,963. These procedures are described below.
Fremgangsmåte ifølge eksempel 8 i belgisk patentskrift nr. 896. 963. Method according to example 8 in Belgian Patent Document No. 896.963.
Forbindelse I, 7-[(dimetylamino)metylen]amino-N<10->(dimetyl-amino )metylen-9a-metoksymitosan ble fremstilt på følgende måte: Til en suspensjon av 500 mg (1,50 mM) mitomycin C i 25 ml kloroform ble tilsatt totalt 9,6 ml (2,4 ml porsjoner etter 0, 18, 21 og 23 timer) N,N-dimetylformamiddimetylacetal, og suspensjonen ble omrørt ved ca. 50°C i 41 timer. Etter avdamping av løsnings-midlet og overskytende reaktant under senket trykk, ble det oppnådd en mørkegrønn rest. Tynnsjiktskromatografi (metylenklorid/metanol = 20:1) påviste fravær av mitomycin C og nærvær av to nye grønne be-standdeler (Rf=0,16 og 0,22). Hovedbestanddelen (Rf=0,16) ble iso-lert ved flash-kromatografi under anvendelse av metylenklorid/ metanol = 20:1 som elueringsmiddel, hvorved det ble oppnådd et grønt fast stoff (340 mg, 51,5%), som ved løsning i dietyleter etterfulgt av tilsetning av heksan gav forbindelse I som et mørkegrønt amorft pulver. Compound I, 7-[(dimethylamino)methylene]amino-N<10->(dimethylamino)methylene-9a-methoxymitosane was prepared as follows: To a suspension of 500 mg (1.50 mM) mitomycin C in 25 ml of chloroform was added to a total of 9.6 ml (2.4 ml portions after 0, 18, 21 and 23 hours) of N,N-dimethylformamide dimethyl acetal, and the suspension was stirred at approx. 50°C for 41 hours. After evaporation of the solvent and excess reactant under reduced pressure, a dark green residue was obtained. Thin-layer chromatography (methylene chloride/methanol = 20:1) demonstrated the absence of mitomycin C and the presence of two new green constituents (Rf=0.16 and 0.22). The main component (Rf=0.16) was isolated by flash chromatography using methylene chloride/methanol = 20:1 as eluent, whereby a green solid (340 mg, 51.5%) was obtained, which on solution in diethyl ether followed by addition of hexane gave compound I as a dark green amorphous powder.
NMR (pyridin d5,6); 2,18 (s, 3H), 2,70 (bs, 1H), 2,76 (s, 3H), 2,82 (s, 3H), 2,86 (s, 6H), 3,22 (s, 3H), 3,30 (bs, 1H), 3,60 (d, J=12Hz), 4,12 (dd, 1H, J=10, 4Hz), 4,43 (d, 1H J=12Hz), 4,90 (bs, 1H), 5,10 (t, 1H, J=10Hz) 5,52 (dd, 1H, J=10, 4Hz), 7,85 (s, 1H), 8,64 (s, 1H). NMR (pyridine d5,6); 2.18 (s, 3H), 2.70 (bs, 1H), 2.76 (s, 3H), 2.82 (s, 3H), 2.86 (s, 6H), 3.22 (s , 3H), 3.30 (bs, 1H), 3.60 (d, J=12Hz), 4.12 (dd, 1H, J=10, 4Hz), 4.43 (d, 1H J=12Hz) , 4.90 (bs, 1H), 5.10 (t, 1H, J=10Hz) 5.52 (dd, 1H, J=10, 4Hz), 7.85 (s, 1H), 8.64 ( pp, 1H).
IR(KBr) <u>maks, cm<-1>: 3300, 2930, 1675, 1620, 1545, 1230, 1060. IR(KBr) <u>max, cm<-1>: 3300, 2930, 1675, 1620, 1545, 1230, 1060.
UV(H2o) xmaks, nm: 390 og 244. UV(H2o) xmax, nm: 390 and 244.
Analyse: beregnet for <c>2i<H>28<N>6°5: C: 56'71' H: 6'08' N: 18,90 Funnet: C: 56,20; H: 6,28; N: 17,88. Analysis: calculated for <c>2i<H>28<N>6°5: C: 56'71' H: 6'08' N: 18.90 Found: C: 56.20; H: 6.28; N: 17.88.
7-(dimetylaminometylen)amino-9a-metoksymitosan (II) ble fremstilt på følgende måte: Til 600 mg (1,35 mM) av forbindelse I løst i 10 ml metanol ble det tilsatt 2,2 ml (10,8 mM) aminodifenylmetan, og den resulterende løsning ble omrørt ved 54°C i 4 timer. Reaksjonsforløpet ble overvåket ved tynnsjiktskromatografi (metylenklorid/metanol = 90:10). Etter ca. 4 timer var utgangsmaterialet (Rf=0,35) for-svunnet, og en dominerende ny grønn sone (Rf=0,29) fremkommet istedenfor. Løsningen ble konsentrert ved senket trykk, og den resulterende viskøse væske ble flash-kromatografert (25 g silikagel) under anvendelse av metylenklorid/metanol = 20:1 som elueringsmiddel. Fraksjoner som inneholdt den grønne bestanddel (Rf=0,29) ble kombinert, tørket (Na2S04> og konsentrert. Forbindelse II ble oppnådd som et amorft fast stoff (215 mg, 41%). 7-(Dimethylaminomethylene)amino-9a-methoxymitosane (II) was prepared as follows: To 600 mg (1.35 mM) of compound I dissolved in 10 ml of methanol was added 2.2 ml (10.8 mM) of aminodiphenylmethane , and the resulting solution was stirred at 54°C for 4 hours. The course of the reaction was monitored by thin-layer chromatography (methylene chloride/methanol = 90:10). After approx. After 4 hours, the starting material (Rf=0.35) had disappeared, and a dominant new green zone (Rf=0.29) appeared instead. The solution was concentrated under reduced pressure and the resulting viscous liquid was flash chromatographed (25 g silica gel) using methylene chloride/methanol = 20:1 as eluent. Fractions containing the green component (Rf=0.29) were combined, dried (Na 2 SO 4 > and concentrated. Compound II was obtained as an amorphous solid (215 mg, 41%).
NMR (pyridin d5,6); 2,18 (s, 3H), 2,70 (bs, 1H), 2,80 (s, 3H), 2,88 (s, 3H), 3,08 (bs, 1H), 3,24 (s, 3h), 3,56 (bd, 1H, J=12Hz), 4,00 (dd, 1H), 4,44 (d, 1H, J=12Hz), 5,06 (t, 1H J=10Hz), 5,56 (dd, 1H, J=10, 4Hz), 7,58 (bs, 2H), 7,88 (s, lH). NMR (pyridine d5,6); 2.18 (s, 3H), 2.70 (bs, 1H), 2.80 (s, 3H), 2.88 (s, 3H), 3.08 (bs, 1H), 3.24 (s , 3h), 3.56 (bd, 1H, J=12Hz), 4.00 (dd, 1H), 4.44 (d, 1H, J=12Hz), 5.06 (t, 1H J=10Hz) , 5.56 (dd, 1H, J=10, 4Hz), 7.58 (bs, 2H), 7.88 (s, 1H).
IR(KBr) umaks, cm_1:3300-3450. 2960-2910, 1715, 1620, 1535, 1050 IR(KBr) umax, cm_1:3300-3450. 2960-2910, 1715, 1620, 1535, 1050
UV(H20) Xmaks, nm: 390 og 226. UV(H20) Xmax, nm: 390 and 226.
Analyse: bergenet for c18H23<N>5<0>5: C,55,48; H:5,91; N:17,98 Analysis: Bergenet for c18H23<N>5<0>5: C.55.48; H: 5.91; N:17.98
Funnet: C:54,83; H:5,67; N:16,90. Found: C:54.83; H: 5.67; N:16.90.
Fremgangsmåte ifølge eksempel 15 i belgisk patentskrift nr. 896, 963 Method according to example 15 in Belgian Patent No. 896, 963
En 0,5 molar løsning av N,N-dimetylklormetyleniminiumklorid ble fremstilt ved dråpevis tilsetning av 1,57 g (12,5 mmol) oksalylklorid ved 0°C til en løsning av 915 mg (12,5 mmol) dimetylformamid i 25 ml CHC13, etterfulgt av omrøring ved romtemperatur i 30 minutter. En løsning av 334 mg (lmmol) mitomycin C i 5 ml dimetylformamid ble separat tilsatt til en suspensjon av 36 mg (1,5 mmol) NaH i 3 ml dimetylformamid. Løsningen ble omrørt ved romtemperatur i 20 minutter og deretter avkjølt til -40°C - -50°C, hvoretter ovennevnte løsning av 3 ml (1,5 mmol) N,N-dimetylklor-metyleniminiumklorid ble tilsatt. Ytterligere NaH (18 mg, 0,75 mmol) ble tilsatt ved -40°C etter omrøring i 10 minutter. Løsningen ble holdt ved en temperatur på -4 0°C i en time, og deretter tynnet med CH2C12 og filtrert. Den etter inndamping av filtratet oppnådde rest ble kromatografert ved tynnsjiktskromatografi på silikagel (10% CH30H-CH2C12 som elueringsmiddel). Ekstraksjon av det dominerende grønne bånd ga 78 mg (43% basert på gjenvunnet mitomycin C) av et amorft fast stoff, hvis NMR-spektrum og tynnsjiktskromatogra-fidata var identisk med spektr\im og data oppnådd for forbindelse II fremstilt som beskrevet ovenfor. A 0.5 molar solution of N,N-dimethylchloromethyleneiminium chloride was prepared by dropwise addition of 1.57 g (12.5 mmol) of oxalyl chloride at 0°C to a solution of 915 mg (12.5 mmol) of dimethylformamide in 25 mL of CHCl 3 , followed by stirring at room temperature for 30 minutes. A solution of 334 mg (lmmol) mitomycin C in 5 ml dimethylformamide was separately added to a suspension of 36 mg (1.5 mmol) NaH in 3 ml dimethylformamide. The solution was stirred at room temperature for 20 minutes and then cooled to -40°C - -50°C, after which the above solution of 3 ml (1.5 mmol) of N,N-dimethylchloro-methyleneiminium chloride was added. Additional NaH (18 mg, 0.75 mmol) was added at -40°C after stirring for 10 min. The solution was kept at a temperature of -40°C for one hour, then diluted with CH 2 Cl 2 and filtered. The residue obtained after evaporation of the filtrate was chromatographed by thin-layer chromatography on silica gel (10% CH3OH-CH2Cl2 as eluent). Extraction of the dominant green band gave 78 mg (43% based on mitomycin C recovered) of an amorphous solid, whose NMR spectrum and thin layer chromatography data were identical to the spectrum and data obtained for compound II prepared as described above.
Krystallinsk 7-(dimetylaminometylen)amino-9a-metoksymitosan fremstilles ifølge oppfinnelsen ved at amorft 7-(dimetylamino-metylen )amino-9a-metoksymitosan oppslemmes i etyleter, og at en liten mengde krystallinsk 7-(dimetylaminometylen)-amino-9a-metoksymitosan deretter tilsettes til omdannelse av den amorfe form av 7-(dimetylaminometylen)amino-9a-metoksymitosan til krystallinsk form. Crystalline 7-(dimethylaminomethylene)amino-9a-methoxymitosane is prepared according to the invention by suspending amorphous 7-(dimethylaminomethylene)amino-9a-methoxymitosane in ethyl ether, and that a small amount of crystalline 7-(dimethylaminomethylene)amino-9a-methoxymitosane is then added to convert the amorphous form of 7-(dimethylaminomethylene)amino-9a-methoxymitosane into crystalline form.
Det etterfølgende eknempel belyser detaljert fremgangsmåten til fremstilling av krystallinsk 7-(dimetylaminometylen)amino-9a-metoksymitosan. The following example illustrates in detail the process for the preparation of crystalline 7-(dimethylaminomethylene)amino-9a-methoxymitosane.
Eksempel Example
1,0 g amorft 7-(dimetylaminometylen)amino-9a-metoksymitosan i fri baseform ble oppslemmet i 10 ml etyleter. En liten mengde, ca. 1.0 g of amorphous 7-(dimethylaminomethylene)amino-9a-methoxymitosane in free base form was slurried in 10 ml of ethyl ether. A small amount, approx.
2 mg, krystallinsk 7-(dimetylaminometylen)amino-9a-metoksymitosan ble tilsatt til blandingen, og blandingen ble omrørt i et lukket system i 48 timer ved 20-25°C. Deretter ble de resulterende mørke-grønne krystaller fjernet ved vakuum-filtrering. Krystallene ble vasket med 10 ml eter og 15 ml "Skellysolve-B" og tørket i høy-vakuum ved 40°C i 24 timer. Utbytte: 0,9 g. 2 mg of crystalline 7-(dimethylaminomethylene)amino-9a-methoxymitosane was added to the mixture and the mixture was stirred in a closed system for 48 hours at 20-25°C. Then the resulting dark-green crystals were removed by vacuum filtration. The crystals were washed with 10 ml of ether and 15 ml of "Skellysolve-B" and dried in high vacuum at 40°C for 24 hours. Yield: 0.9 g.
Analyse beregnet for ci8<H>23<N>5°5: C: 55'48; H: 5'9; N:17,989 Analysis calculated for c18<H>23<N>5°5: C: 55'48; Height: 5'9; N:17,989
Funnet: C: 55,11, 5,37; H: 5,88, 5,93; Found: C: 55.11, 5.37; H: 5.88, 5.93;
N: 17,6, 17,7 N: 17.6, 17.7
Dette materiale hadde et IR-spektrum som vist på tegningen. IR-spektret ble opptatt fra en prøve i en presset kaliumbromid-. skive. Et NMR-spektrum ble bestemt ved 90 MHz for proton ('H NMR). NMR-spektret ga følgende J-verdier: This material had an IR spectrum as shown in the drawing. The IR spectrum was taken from a sample in a pressurized potassium bromide-. slice. An NMR spectrum was determined at 90 MHz for proton (1 H NMR). The NMR spectrum gave the following J values:
En løsning i metanol av 0,01625 g av materialet pr. liter ga følgende karakteristika ved IR-spektrometri: A solution in methanol of 0.01625 g of the material per liter gave the following characteristics by IR spectrometry:
Stabiliteten til 7-(dimetylaminometylen)amino-9a-metoksymitosan ble bestemt ved følgende fremgangsmåte: Nøyaktig avveide mengder i området fra 5 til 2 5 mg 7-(dimetylaminometylen)amino-9a-metoksymitosan ble anbragt i det nødvendige antall 3,6 ml glass med skrulokk. Det nødvendige antall glass med skrulokk som inneholdt nøyaktig oppveiet 7-(dimetylaminometylen)amino-9a-metoksymitosan ble anbragt under forskjellige temperaturbetingelser. For hvert tid-temperaturintervall ble et glass som inneholdt forut oppveiet 7-(dimetylaminometylen)amino- 9a-metoksymitosan underkastet høytrykksvæskekromatografi-analyse. Resultatet av denne er angitt som mikrogram/mg 7-(dimetylaminometylen)amino^9a-metoksymitosan-aktivitet. Resultatene fremgår av tabellen. I tabellen angir tallene i parantes de prosentvise tap av amorft 7-(dimetylamino-metylen) amino-9a- metoksymitosan. The stability of 7-(dimethylaminomethylene)amino-9a-methoxymitosane was determined by the following procedure: Accurately weighed amounts in the range from 5 to 25 mg of 7-(dimethylaminomethylene)amino-9a-methoxymitosane were placed in the required number of 3.6 ml glasses with screw cap. The required number of screw cap vials containing precisely weighed 7-(dimethylaminomethylene)amino-9a-methoxymitosane were placed under different temperature conditions. For each time-temperature interval, a glass containing previously weighed 7-(dimethylaminomethylene)amino-9α-methoxymitosane was subjected to high pressure liquid chromatography analysis. The result of this is indicated as micrograms/mg 7-(dimethylaminomethylene)amino^9a-methoxymitosan activity. The results appear in the table. In the table, the numbers in parentheses indicate the percentage loss of amorphous 7-(dimethylaminomethylene)amino-9a-methoxymitosane.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO890809A NO164241C (en) | 1985-02-21 | 1989-02-27 | PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC 7- (DIMETHYLAMINOMETHYL) AMINO-9A METOXYMITOSAN. |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/703,778 US4639528A (en) | 1985-02-21 | 1985-02-21 | Crystalline form of 7-(dimethylaminomethylene-amino-9a-methoxymitosane |
| NO860633A NO162021C (en) | 1985-02-21 | 1986-02-20 | PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC 7- (DIMETHYLAMINOMETHYL) AMINO-9A METOXYMITOSAN. |
| NO890809A NO164241C (en) | 1985-02-21 | 1989-02-27 | PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC 7- (DIMETHYLAMINOMETHYL) AMINO-9A METOXYMITOSAN. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO890809L NO890809L (en) | 1986-08-22 |
| NO890809D0 NO890809D0 (en) | 1989-02-27 |
| NO164241B true NO164241B (en) | 1990-06-05 |
| NO164241C NO164241C (en) | 1990-09-12 |
Family
ID=27352960
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO890809A NO164241C (en) | 1985-02-21 | 1989-02-27 | PROCEDURE FOR THE PREPARATION OF CRYSTALLINIC 7- (DIMETHYLAMINOMETHYL) AMINO-9A METOXYMITOSAN. |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO164241C (en) |
-
1989
- 1989-02-27 NO NO890809A patent/NO164241C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO890809D0 (en) | 1989-02-27 |
| NO890809L (en) | 1986-08-22 |
| NO164241C (en) | 1990-09-12 |
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