CN103242210B - Mulin acetate containing substituted squaric acid and application thereof - Google Patents
Mulin acetate containing substituted squaric acid and application thereof Download PDFInfo
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- CN103242210B CN103242210B CN201210028544.XA CN201210028544A CN103242210B CN 103242210 B CN103242210 B CN 103242210B CN 201210028544 A CN201210028544 A CN 201210028544A CN 103242210 B CN103242210 B CN 103242210B
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Abstract
The invention relates to Mulin acetate containing substituted squaric acid and an application thereof which belong to the technical field of medicines, specifically to substituted squaric acid containing Mulin acetate as shown in a general formula (I), pharmaceutically acceptable salt, a hydrate and an isomer thereof, wherein R1, R2, R3, R4, R5 and B are defined in the specification. The invention also relates to a preparation method of these compounds, a pharmaceutical composition containing these compounds and an application of these compounds in the preparation of drugs for treating or preventing bacteria and virus. As for staphylococcus aureus and Streptococcus equin MIC value, the compounds have an antibacterial effect 15-20 times higher than a control commercially-available antibiotic tiamulin in the test. And the compounds provided by the invention are effective antimicrobial agents. And the compounds provided by the invention are effective antimicrobial agents.
Description
Technical field
The invention belongs to medical technical field, relate to the wonderful woods ester of the sour acetic acid in replacement side, its pharmacy acceptable salt, its hydrate, and isomer; The invention still further relates to the preparation method of these compounds, the pharmaceutical composition that contains these compounds, and these compounds preparation treatment/or prevent antibacterial, the application in antiviral drug.
Background technology
Since penicillin is found, the history of the mankind to the existing last 100 years of the research of antibiotic.During this period, the research of antibacterial new drug mainly concentrates on the medicines such as beta-lactam, Macrolide and quinolones.The discovery of anti-microbial type medicine, greatly improved the mankind's healthy living level, but consequent abuse of antibiotics has caused the appearance of resistance.Until the nineties in 20th century, the development of resistance and expansion just make people recognize the seriousness of this problem, and the mankind's healthy and existence has been arrived in the serious threat of antibiotic resistance problem.In the recent period, the continuous appearance of various " superbacterias " with resistance, especially for people have beaten alarm bell, impels the mankind urgently to wish to find novel antibacterial medicine, propagates and resistance problem with the big area of tackling " superbacteria " that may occur.One of them effective strategy be exactly find before reappraising Resistant strain is had to excellent activity, but not yet for mankind's antibacterials.
Pleuromutilin (Pleuromutilin) is the tricyclic diterpene carbapenem antibiotic by a class wide spectrum of higher fungi basidiomycetes pleurotus Pleurotus mutilus and the generation of plenrots passeckerianus bacterium, is the bulk drug of the semi-synthetic derivative of pleuromulins.The important pleuromulins antibacterials for animals of listing comprise safe second rhzomorph (Tiamulin) and valnemulin (Valnemulin) at present.In April, 2007, auspicious his the wonderful woods (Retapmulin) of GlaxoSmithKline PLC (GSK) company is ratified listing (pleuromutilin and marketed drug structure thereof are as follows) by U.S. food and drug surveilance office (FDA).Auspicious his wonderful woods carrys out first brand-new local people's antibacterials as recent two decades, and its approval listing means a great, and this indicates that pleuromutilin derivative realized the leap from veterinary medicine to people's medication.Nabriva and GSK drugmaker be the lasting input with oral antibiotic research and development to pleuromulins people, is also indicating the good DEVELOPMENT PROSPECT that this type of medicine has.
The antibacterial mechanisms of pleuromutilin analog derivative: pleuromutilin and derivative thereof are by selectivity and the effect of prokaryotic organism rrna, thereby the synthetic restraining effect realizing bacterium of interference bacterioprotein, and do not affect the synthetic of eukaryotic protein.To having obtained the single crystal structure of Tiamulin and Deinococcus radiodurans (Deinococus radiodurans) 50S ribosomal subunit mixture in the research process of Tiamulin and valnemulin, directly disclose the antibacterial mechanisms of pleuromutilin analog derivative.Tiamulin is bonded near the upper site, peptidyl transferase center of the large small subunit intersection of rrna with the molecular ratio of 1: 1, mainly by the activity of inhibiting peptide based transferase, protein synthesis is obstructed, thereby reaches fungistatic effect.
At present, the pleuromulins antimicrobial drug that is hopeful listing also has BC-3205, BC-3781 and the BC-7013 (structural formula is as follows) by Nabriva Therapeutics company exploitation.BC-3205 has good effect to resistant organism, and penicillin-fast streptococcus pneumoniae and methicillin-resistant staphylococcus aureus (MRSA) are had to good bacteriostatic action, and the probability of it and other antimicrobial drug generation crossing drug resistants is very low.It is worth mentioning that, BC-3205 both can external application also can be oral, it is in I phase clinical study at present.In July, 2009, Nabriva Therapeutics has started security and the tolerance I phase of BC-3781 and has studied, and BC-3781 is that pleuromutilin produces mycoprotein matter synthetic inhibitor, intends being used for the treatment of bacterium and infects.The said firm wishes that it selects medicine can be effective to skin and complex structure infection, community acquired pneumonia, methicillin-resistant staphylococcus aureus and other Resistant strain.The special feature of BC-3781 is, it is first-generation pleuromutilin, and oral and vein scheme is once a day provided, and opened the possibility of pleuromutilin from vein to oral " degradation treatment ".At present, BC-3781 has completed the volunteer recruiting of clinical II phase, is about to carry out II clinical trial phase.BC7013 also has good bacteriostatic action to above resistant organism, and its security is better
[20].2008, BC7013, as externally applied agent, completed I phase clinical study.
Find new efficient microbiotic, be all important tasks of medical scientific research work always.Therefore we wish further to find the new pleuromulins compound with high-efficiency antimicrobial activity
Summary of the invention
The invention provides a kind of wonderful woods ester cpds that contains the acid of replacement side, the commercially available antibiotic that it takes one's test than contrast to golden Portugal bacterium, strangles streptococcus m IC value---the high 15-25 of fungistatic effect of Tiamulin doubly, is high-efficiency antimicrobial medicine.
Compound shown in general formula (I), its pharmacy acceptable salt, solvate or its isomer, or the prodrug of described compound prodrug or described salt,
Wherein, R
1, R
2, R
3, R
4, R
5independently represent respectively hydrogen atom, carboxyl, C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, amide group, N-(C
1-6alkyl) substituted amido or R
1, R
2, R
3, R
4, R
5between the two, be interconnected to form arbitrarily the first saturated or undersaturated 0-4 of containing the heteroatomic cyclic group of substituted or non-substituted 3-8,
B represents OR
6, SR
7or NR
8r
9; Wherein R
6, R
7, R
8, R
9independently represent respectively hydrogen atom, the C being replaced by 0～1 substituting group W
1-6alkyl, the C being replaced by 0～1 substituting group W
2-6thiazolinyl, the C being replaced by 0～1 substituting group W
2-6alkynyl, the C being replaced by 0～1 substituting group W
1-6alkyl-carbonyl, the C being replaced by 0～1 substituting group W
3-8cycloalkyl, the C being replaced by 0～1 substituting group W
1-6alkyl acyl, the C being replaced by 0～1 substituting group W
1-6alkyl sulphonyl, or R
8with R
9be interconnected to form the first saturated or undersaturated 0-4 of containing the heteroatomic cyclic group of substituted or non-substituted 3-8,
Described substituting group W is independently selected from hydroxyl, amino, carboxyl, guanidine radicals, sulfonic group, phosphate, sulfoamido, C
1-6alkoxyl group, C
1-6alkylthio ,-NHR
10,-NR
11r
12; Wherein substituent R
10, R
11, R
12independently be selected from respectively C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl, or R
11with R
12be interconnected to form the first saturated or undersaturated 0-4 of containing the heteroatomic cyclic group of substituted or non-substituted 3-8,
Described heteroatoms can be respectively independent or be selected from O, N or S simultaneously.
Described compound or its pharmacy acceptable salt, solvate, isomer or its prodrug, its structural formula is as shown in (II):
Wherein, R
1, represent hydrogen atom, C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl;
Preferred: R1 represents hydrogen atom, C
1-6alkyl, B represents OR
6, SR
7or NR
8r
9; Wherein R
6, R
7, R
8, R
9independently represent respectively hydrogen atom, the C being replaced by 0～1 substituting group W
1-6alkyl, the C being replaced by 0～1 substituting group W
1-6alkyl-carbonyl, the C being replaced by 0～1 substituting group W
3-8cycloalkyl, the C being replaced by 0～1 substituting group W
1-6alkyl acyl, or R
8with R
9be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described substituting group W is independently selected from hydroxyl, amino, carboxyl, guanidine radicals, C
1-6alkoxyl group, C
1-6alkylthio ,-NHR
10,-NR
11r
12; Wherein substituent R
10, R
11, R
12independently be selected from respectively C
1-6alkyl, or R
11with R
12be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described heteroatoms can be respectively independent or be selected from O, N or S simultaneously.
Above-claimed cpd or its pharmacy acceptable salt, solvate, isomer or its prodrug, its structural formula is as shown in (III):
Preferred: B represents OR
6, SR
7or NR
8r
9; R
6, R
7, R
8, R
9independently represent respectively hydrogen atom, the C being replaced by 0～1 substituting group W
1-6alkyl, the C being replaced by 0～1 substituting group W
1-6alkyl-carbonyl, the C being replaced by 0～1 substituting group W
3-8cycloalkyl, the C being replaced by 0～1 substituting group W
1-6alkyl acyl, or R
8with R
9be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described substituting group W is independently selected from hydroxyl, amino, carboxyl, guanidine radicals, C
1-6alkoxyl group, C
1-6alkylthio ,-NHR
10,-NR
11r
12; Wherein substituent R
10, R
11, R
12independently be selected from respectively C
1-6alkyl, or R
11with R
12be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described heteroatoms can be respectively independent or be selected from O, N or S simultaneously.
Above-mentioned compound or its pharmacy acceptable salt, solvate, isomer or its prodrug, its structural formula is as shown in (IV):
Preferred: B represents OR
6, SR
7or NR
8r
9; Wherein R
6, R
7, R
8, R
9independently represent respectively hydrogen atom, the C being replaced by 0～1 substituting group W
1-6alkyl, the C being replaced by 0～1 substituting group W
2-6thiazolinyl, the C being replaced by 0～1 substituting group W
2-6alkynyl, the C being replaced by 0～1 substituting group W
1-6alkyl-carbonyl, the C being replaced by 0～1 substituting group W
3-8cycloalkyl, the C being replaced by 0～1 substituting group W
1-6alkyl acyl, or R
8with R
9be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described substituting group W is independently selected from hydroxyl, amino, carboxyl, guanidine radicals, C
1-6alkoxyl group, C
1-6alkylthio ,-NHR
10,-NR
11r
12; Wherein substituent R
10, R
11, R
12independently be selected from respectively C
1-6alkyl, or R
11with R
12be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described heteroatoms can be respectively independent or be selected from O, N or S simultaneously.
Above-mentioned compound or its pharmacy acceptable salt, solvate, isomer or its prodrug, its structural formula is as shown in (V):
Q is selected from O, S, NR
13; Wherein R
13represent hydrogen atom, C
1-6alkyl, C
1-6alkyl acyl, C
2-6thiazolinyl, C
2-6alkynyl.
Preferred: Q is selected from O, S, NR
13; Wherein R
13represent hydrogen atom, C
1-6alkyl.
B represents OR
6, SR
7or NR
8r
9; Wherein R
6, R
7, R
8, R
9independently represent respectively hydrogen atom, the C being replaced by 0～1 substituting group W
1-6alkyl, the C being replaced by 0～1 substituting group W
1-6alkyl-carbonyl, the C being replaced by 0～1 substituting group W
3-8cycloalkyl, the C being replaced by 0～1 substituting group W
1-6alkyl acyl, or R
8with R
9be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described substituting group W is independently selected from hydroxyl, amino, carboxyl, guanidine radicals, C
1-6alkoxyl group, C
1-6alkylthio ,-NHR
10,-NR
11r
12; Wherein substituent R
10, R
11, R
12independently be selected from respectively C
1-6alkyl, or R
11with R
12be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described heteroatoms can be respectively independent or be selected from O, N or S simultaneously.
Above-mentioned compound or its pharmacy acceptable salt, solvate, isomer or its prodrug, its structural formula is as shown in (VI):
Wherein, R
1, represent hydrogen atom, C
1-6alkyl, C
2-6thiazolinyl, C
2-6alkynyl; M representation carboxy, amide group; N-(C
1-6alkyl) substituted amido.
Preferred: B represents OR
6, SR
7or NR
8r
9; Wherein R
6, R
7, R
8, R
9independently represent respectively hydrogen atom, the C being replaced by 0～1 substituting group W
1-6alkyl, the C being replaced by 0～1 substituting group W
1-6alkyl-carbonyl, the C being replaced by 0～1 substituting group W
3-8cycloalkyl, the C being replaced by 0～1 substituting group W
1-6alkyl acyl, or R
8with R
9be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described substituting group W is independently selected from hydroxyl, amino, carboxyl, guanidine radicals, C
1-6alkoxyl group, C
1-6alkylthio ,-NHR
10,-NR
11r
12; Wherein substituent R
10, R
11, R
12independently be selected from respectively C
1-6alkyl, or R
11with R
12be interconnected to form substituted or non-substituted 3-8 unit saturated contain 0-4 heteroatomic cyclic group, described heteroatoms can be respectively independent or be selected from O, N or S simultaneously.
Above-claimed cpd or its pharmacy acceptable salt, solvate, isomer or its prodrug, preferred compound can be selected from:
The pharmacy acceptable salt of above-claimed cpd, it is characterized in that pharmaceutically acceptable.Comprise organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts;
Particular certain cancers, sylvite, calcium salt.
A kind of pharmaceutical composition, by above-mentioned compound and pharmacy acceptable salt thereof, solvate, or its isomer, with one or more pharmaceutical carriers and/or thinner composition.
Described pharmaceutical composition, is characterized in that containing the above-mentioned compound of 0.01～10g and pharmacy acceptable salt thereof or its isomer as essential activeconstituents.
Above-mentioned compound and pharmacy acceptable salt thereof, solvate, or its isomer or pharmaceutical composition, preparation, treatment or prevention animal antibacterial, the application in antiviral drug.
Wherein indication animal is the mankind or other Mammalss or poultry.
The wherein preferred ox of other Mammalss, Ma Heyang.
Above-mentioned compound and pharmacy acceptable salt thereof, the preparation method of solvate or its isomer, comprises the steps: that (1) provides compound
(2) react and obtain by following formula
The above-mentioned arbitrary compound pharmacy acceptable salt of the present invention refers to by pharmaceutically acceptable, and the salt of non-toxic bases or acid preparation, comprises organic acid salt, inorganic acid salt, organic alkali salt or inorganic base salts.Organic acid comprises acetic acid, Phenylsulfonic acid, phenylformic acid, tosic acid, butene dioic acid, (2R, 3R) 2,3 dyhydrobutanedioic acids, camphorsulfonic acid, citric acid, ethyl sulfonic acid, fumaric acid, glyconic acid, L-glutamic acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, pamoic acid, pantothenic acid, succsinic acid, tartrate.Mineral acid comprises Hydrogen bromide, spirit of salt, nitric acid, sulfuric acid, phosphoric acid etc., particularly preferably Hydrogen bromide, spirit of salt, nitric acid, sulfuric acid, phosphoric acid.Organic bases comprises the primary, and the second month in a season, tertiary amine, is substituted amine and comprises naturally occurring replacement amine, cyclammonium and basic ion exchange resin, be selected from arginine, trimethyl-glycine, caffeine, choline, N, N '-dibenzyl-ethylenediamin, diethylamine, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, meglumine, glucosamine, Histidine, Hai Baming, isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, polyamides resin, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.Mineral alkali comprises ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, barium, aluminium, iron, copper, ferrous iron, manganese, the basic cpd of bivalent manganese etc., particularly preferably ammonium and lithium, sodium, potassium, calcium, magnesium, zinc, the basic cpd of barium.
The compounds of this invention or contain one or more asymmetric centers, thereby can be used as racemic modification and racemic mixture, single enantiomer, non-enantiomer mixture and single diastereomer.The compounds of this invention or have asymmetric center, this class asymmetric center respectively will independently produce two optical isomers, and scope of the present invention comprises all possible optical isomer and non-enantiomer mixture and pure or partial-purified compound.The present invention includes all isomeric forms of these compounds.Part of compounds of the present invention can exist with tautomeric forms, and it has the different tie points of hydrogen by one or more both shoulders displacement.For example, ketone and its enol form are keto-enol tautomers.Each tautomer and composition thereof is included in compound of the present invention.
Compound of the present invention can be combined with one or more other drugs, more safer or more effective than single medicine.Can be by these other drugs and formula (I), (II) or (III) compound is simultaneously or in succession by a kind of approach and with its usual amounts administration.When simultaneously administration, be preferably contained other drug and formula (I), (II) or (III) medicinal compositions of the unit dosage form of compound.Can with formula (I), (II) or (III) compound drug combination, respectively administration or in same medicinal compositions other activeconstituentss of administration comprise, but be not limited to: (a), other antibacterials, (b), other antiviral, (c), other anti-inflammatory medicaments
The invention still further relates to a kind of pharmaceutical composition, described pharmaceutical composition comprises compound and a kind of pharmaceutically acceptable carrier of general formula (I).For example, pharmaceutical composition can be with tablet, capsule, pill, powder, sustained release dosage, solution, the form oral administration of suspension; Pharmaceutical composition also can be with sterile liquid, the form parenteral injection administration of suspension or emulsion; Pharmaceutical composition also can be with the form topical of ointment or white cream; Pharmaceutical composition also can be with the form rectal administration of suppository.Pharmaceutical composition can be made unit dosage, and it is suitable for the single administration of exact dosage desired.Pharmaceutical composition comprises conventional pharmaceutical carrier or vehicle and the compound of the present invention as active part.In addition, pharmaceutical composition can comprise medical science or pharmaceutical formulations, carrier, auxiliary agent etc.
All used definition and the embodiment of the functional group of time column selection in the whole text with in claims at specification sheets of the present invention, they are used for illustrating the present invention and unrestricted the present invention.
Term " alkyl " refers to straight or branched saturated hydrocarbyl.The example of some alkyl is methyl, ethyl, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group and hexyl.
Term " cycloalkyl " refers to saturated or undersaturated ring texture alkyl, unless otherwise mentioned, is monocycle.Some examples of cycloalkyl comprise cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Some examples of cycloalkenyl group comprise cyclopropenyl radical, cyclobutene base, cyclopentenyl and cyclohexenyl.
Term " alkenyl " represents the straight or branched unsaturated alkyl of at least two carbon.Some examples of alkenyl are vinyl, propenyl and isobutenyl.
Term " alkynyl " is illustrated in the straight or branched alkyl that at least comprises a triple bond between two carbon atoms.Some examples of alkynyl are ethynyls, for example propine-1-base of proyl and propine-2-base and propine-3-base.
Term " alkoxyl group " represents the straight or branched alkyl connecting by Sauerstoffatom.Some examples of alkoxyl group are methoxyl groups, oxyethyl group, propoxy-, isopropoxy, butoxy, isobutoxy, pentyloxy and hexyloxy.
Term " acyl group " represents the straight or branched hydrocarbyl portion connecting by carbonyl.Some examples of acyl group are ethanoyl, propionyl, butyryl radicals and isobutyryl.
Term " alkylthio (alkythio) " represents a kind of alkyl connecting by sulphur atom.Some examples of alkylthio are methylthio groups, ethylmercapto group, rosickyite base, isopropyl sulfenyl, butylthio, isobutyl sulfenyl, penta sulfenyl and own sulfenyl.
The present invention also provides the preparation method of above-claimed cpd, shown in following scheme-1, but is not limited only to following method.
In the following discussion, abbreviation and abbreviation in the present invention's chemistry and program, comprise Me (methyl); Et (ethyl); EtOAc (ethyl acetate); THF (tetrahydrofuran (THF)); DMF (dimethyl formamide); DMAP (4-dimethylamino pyridine); Ms (methylsulfonyl); DIEA (diisopropylethylamine); BOC (tertbutyloxycarbonyl); TFA (trifluoroacetic acid); Ac (ethanoyl); Eq (equivalent); RP (anti-phase); HPLC (high performance liquid chromatography); TLC (thin-layer chromatography).
B in following reaction equation, M, W, Q, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12the group of representative as mentioned before.
Scheme-1
The method of general formula (I) target compound is prepared in scheme-1 explanation.First from 2-amino alcohol; through 2 step reactions, amino wherein and hydroxyl are protected by protecting group; intermediate-3 that obtain are reacted and are obtained intermediate-4 with the wonderful woods ester of raw material alpha mercaptoacetic acid of process transformation, then under acidic conditions, remove amino protecting group and obtain intermediate-5.Then carry out substitution reaction from raw material-3 side's diethyl phthalate with raw material B-H and obtain intermediate-6, intermediate-6 are reacted with intermediate-5 and obtained ultimate aim compound.Part target compound need to further be sloughed blocking group and just can obtain.Reactions steps:
step 1: the preparation of intermediate-2
0.1 mole of raw material-1 is dissolved in 200 milliliters of methylene dichloride (or tetrahydrofuran (THF)), add 0.15 mole of triethylamine or other alkali (organic bases or mineral alkali), under stirring at room temperature, add 0.12 mole of Boc acid anhydrides, within stirring at room temperature 6-12 hour, disappear to raw material-1, add 100 milliliters of saturated aqueous ammonium chlorides, stir 1 hour.Separating funnel separates dichloromethane layer, and 50 milliliters of dichloromethane extractions 2 times for water layer merge after 100 milliliters of washed twice of organic layer saturated aqueous common salt, organic layer is dry with Magnesium Chloride Anhydrous, filters, and is spin-dried for solvent and obtains intermediate-2 crude product, be directly used in next step reaction, productive rate is between 85-96%.
step 2: the preparation of intermediate-3
0.05 mole of raw material-2 is dissolved in 150 milliliters of methylene dichloride, add 0.06 mole of triethylamine or other organic basess, ice-water bath is cooled to 0 DEG C, slowly drip 0.06 mole of methane SULPHURYL CHLORIDE, dropwise 0 DEG C of stirring reaction 5-6 of rear maintenance hour and disappear to raw material-2, at 0 DEG C, drip 20-30 milliliter saturated aqueous ammonium chloride cancellation reaction.Separating funnel separates dichloromethane layer, 50 milliliters of dichloromethane extractions 2 times for water layer, merge the washing of organic layer saturated aqueous common salt 30-50 milliliter after organic layer Magnesium Chloride Anhydrous dry, filter, be spin-dried for solvent and obtain intermediate-3 crude product, be directly used in next step reaction, productive rate is between 80-95%.
step 3: the preparation of intermediate-4
0.05 mole compound-3 are dissolved in 100 milliliters of dry DMF, in stirring, add behind 0.05 mole of raw material-2, at room temperature reaction 6-24 hour, add 100 ml water cancellation reactions, then use dichloromethane extraction (100 milliliters × 3), organic layer is dry with Magnesium Chloride Anhydrous, filter, be spin-dried for solvent and obtain intermediate-4 crude product, then with ethyl acetate or ether recrystallization, obtain intermediate 4 sterlings, productive rate is between 60-90%.
step 4: the preparation of intermediate-5
0.01 mole compound-4 are dissolved in 100 milliliters of anhydrous diethyl ethers, under stirring, pass into dry HCl gas, produce gradually white precipitate to not till producing precipitation, filtration under diminished pressure, the vacuum-drying of gained solid, obtains intermediate-5 sterling, and productive rate is between 80-90%.
step 5: the preparation of intermediate-6
0.1 mole of raw material-3 and 0.12 moore reactant BH are dissolved in 200 milliliter 1, in 2-ethylene dichloride (or ether), at 40-50 DEG C, react after being chilled to room temperature after 12 hours and go to separating funnel, dry with organic layer Magnesium Chloride Anhydrous after 20 milliliters of saturated sodium bicarbonate aqueous solution washings, filter, be spin-dried for solvent and obtain intermediate-6 crude product, underpressure distillation or column chromatography purification obtain intermediate-6 sterling, and productive rate is between 60-90%.
step 6: the preparation of end product
0.02 mole compound-6 and 0.025 mole compound-5 are dissolved in 50 milliliters of dehydrated alcohols, add after excessive triethylamine or other organic bases, at 40-50 DEG C, react after 12 hours, be chilled to room temperature, go to separating funnel, with after 10 milliliters of saturated sodium bicarbonate aqueous solution washings, organic layer is dry with Magnesium Chloride Anhydrous, filters, decompression is spin-dried for solvent, obtain end product crude product, obtain end product through further recrystallization or column chromatography purification, productive rate is between 60-90%.
Embodiment
The embodiment of form by the following examples, is described in further detail foregoing of the present invention.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following examples.All technology realizing based on foregoing of the present invention all belong to scope of the present invention.Embodiment 1:2-(1-(2-amino-3,4-dioxo cyclobutene-1-yl) amino-2-methyl propyl group) Thiovanic acid (3aS, 4R, 5S, 6s, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, it is tabular compound 1 that 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester
the preparation of step 1:N-tertbutyloxycarbonyl-2-hydroxyl-2 methyl propylamine
1-amino-2-methyl propyl alcohol (8.9g, 0.1mol) be dissolved in 200 milliliters of methylene dichloride, add triethylamine (15.2g, 0.15mol), under stirring at room temperature, add Boc acid anhydrides (26.2g, 0.12mol), stirring at room temperature 8 hours to raw material disappears, add 100 milliliters of saturated aqueous ammonium chlorides, stir 1 hour.Separating funnel separates dichloromethane layer, 50 milliliters of dichloromethane extractions 2 times for water layer, merge after 100 milliliters of washed twice of organic layer saturated aqueous common salt, organic layer is dry with Magnesium Chloride Anhydrous, filter, be spin-dried for solvent and obtain N-tertbutyloxycarbonyl-2-hydroxyl-2 methyl propylamine crude product, be directly used in next step reaction (17.2g, 91%).
1H?NMR(400MHz，CDCl
3)δ8.35(br.s，1H)，3.26(s，2H)，1.93(br.s，1H)，1.37(s，9H)，1.22(s，6H)；LC-MS?m/z＝190[M+H]
+。
the preparation of step 2:N-tertbutyloxycarbonyl-2-hydroxyl-2 methyl propylamine methanesulfonates
By gained compound-2 crude product (9.45g in step 1,0.05mol) be dissolved in 150 milliliters of methylene dichloride, add 0.06 mole of triethylamine, ice-water bath is cooled to 0 DEG C, slowly drip methane sulfonyl chloride (6.84g, 0.06mol), dropwise 0 DEG C of stirring reaction of rear maintenance 5 hours to raw material and disappear, at 0 DEG C, drip 20 milliliters of saturated aqueous ammonium chloride cancellation reactions.Separating funnel separates dichloromethane layer, and 50 milliliters of dichloromethane extractions 2 times for water layer merge organic layer.Organic phase is with after 50 milliliters of washings of saturated aqueous common salt, and Magnesium Chloride Anhydrous is dry, filters, and is spin-dried for solvent and obtains compound-3 crude product, is directly used in next step reaction (11.6g, 87%).
1H?NMR(400MHz，CDCl
3)δ8.52(br.s，1H)，3.31(s，2H)，3.06(s，3H)，1.61(s，6H)，1.42(s，9H)；LC-MS?m/z＝268[M+H]
+。
step 3:2-(1-N-t-butoxycarbonyl amino-2-methyl-prop-2-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl
-4,6,9,10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester
The compound obtaining in step 23 (13.35g, 0.05mol) is dissolved in 100 milliliters of dry DMF, in stirring, adds raw material-2 (19.7g, 0.05mol), room temperature reaction 18 hours, add 100 ml water cancellation reactions, then use dichloromethane extraction (100 milliliters × 3), organic layer is dry with Magnesium Chloride Anhydrous, filter, be spin-dried for solvent and obtain compound-4 crude product, re-crystallizing in ethyl acetate, obtain compound-4 sterling (17.2g, 61%).
1H?NMR(400MHz，CDCl
3)δ8.31(br.s，1H)，6.52(dd，1H)，5.76(d，1H)，5.33(d，1H)，5.31(d，1H)，3.85(s，2H)，3.42(s，2H)，3.28-3.32(m，1H)，2.05-2.29(m，4H)，1.66-1.71(m，1H)，1.63-1.65(m，2H)，1.62(s，3H)，1.61(s，6H)，1.41-1.46(m，14H)，1.29-1.33(m，2H)，1.22(s，3H)，0.86(d，3H)，0.68(d，3H)；LC-MS?m/z＝566[M+H]
+。
step 4:2-(1-amino-2-methyl third-2-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-
vinyl-3a, 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester hydrochloride
By the compound-4 (5.65g obtaining in step 2,0.01mol) be dissolved in 100 milliliters of anhydrous diethyl ethers, under stirring at room temperature, pass into dry HCl gas, produce gradually white precipitate to not till producing precipitation, filtration under diminished pressure, the vacuum-drying of gained solid, obtains compound-5 (4.56g, 91%).
1H?NMR(400MHz，CD
3OD)δ6.55(dd，1H)，5.81(d，1H)，5.36(d，1H)，5.34(d，1H)，3.79(s，2H)，3.37(s，2H)，3.29-3.33(m，1H)，2.10-2.34(m，4H)，1.69-1.74(m，1H)，1.65-1.67(m，2H)，1.64(s，3H)，1.60(s，6H)，1.45-1.49(m，5H)，1.33-1.37(m，2H)，1.25(s，3H)，0.86(d，3H)，0.71(d，3H)；LC-MS?m/z＝502[M+H]
+。
step 5:3-amino-4-oxyethyl group-3-cyclobutene-1, the preparation of 2-diketone
Side's diethyl phthalate (17.0g, 0.1mol) is dissolved in 200 milliliters of anhydrous diethyl ethers, blasts dry ammonia under room temperature, separate out gradually white precipitate, filtration under diminished pressure, obtains 3-amino-4-oxyethyl group-3-cyclobutene-1 after being dried, 2-diketone (11.6g, 82%).
1H?NMR(400MHz，CDCl
3)δ8.57(br.s，2H)，4.05(q，2H)，1.13(t，3H)；LC-MS?m/z＝142[M+H]
+。
step 6:2-(1-(2-amino-3,4-dioxo cyclobutene-1-yl) amino-2-methyl third-2-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-eight
hydrogen-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester
3-amino-4-oxyethyl group-3-cyclobutene-1,2-diketone (1.41g, 0.01mol) be dissolved in 30 milliliters of dehydrated alcohols, add after 1.5mL triethylamine, then add compound-5 (5.02g, 0.01mol) that obtain in step 4, room temperature reaction 18 hours, evaporated under reduced pressure solvent, purification by silica gel column chromatography must be to sterling (4.3g, 77%).
1H?NMR(400MHz，CDCl
3)δ8.35(br.s，2H)，7.91(br.s，1H)，6.51(dd，1H)，5.77(d，1H)，5.35(d，1H)，5.32(d，1H)，3.71(s，2H)，3.28-3.30(m，1H)，3.16(s，2H)，2.08-2.32(m，5H)，1.66-1.87(m，4H)，1.62-1.65(m，3H)，1.58(s，6H)，1.42-1.46(m，3H)，1.31-1.34(m，2H)，1.24(s，3H)，0.88(d，3H)，0.66(d，3H)；LC-MS?m/z＝561[M+H]
+。
Embodiment 2:2-(1-(2-(piperazine-1-yl)-3,4-dioxo cyclobutene-1-yl) amino-2-methyl propyl group) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, it is tabular compound 07 that 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester
step 1:3-(piperazine-1-yl)-4-oxyethyl group-3-cyclobutene-1, the preparation of 2-diketone
By the square diethyl phthalate (1.7g obtaining in embodiment 1,0.01mol) be dissolved in 30 milliliters of dehydrated alcohols, add piperazine (0.86g, 0.01mol), after heating reflux reaction 12 hours, after concentrating under reduced pressure, add 50 milliliters of ether, stir, separate out white solid, filtration under diminished pressure, after dry, obtain 3-(piperazine-1-yl)-4-oxyethyl group-3-cyclobutene-1,2-diketone (1.49g, 71%).
1H?NMR(400MHz，CDCl
3)δ4.06(q，2H)，2.32(t，4H)，2.18(t，4H)，1.96(br.s，1H)，1.21(t，3H)；LC-MS?m/z＝211[M+H]
+。
step 2:2-(1-(2-(piperazine-1-yl)-3,4-dioxo cyclobutene-1-yl) amino-2-methyl third-2-yl) Thiovanic acid
(3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircle penta cyclooctene-1 (4H)-
the preparation of ketone-8-ester
By the 3-obtaining in step 1 (piperazine-1-yl)-4-oxyethyl group-3-cyclobutene-1,2-diketone (1.05g, 0.005mol) be dissolved in 30 milliliters of dehydrated alcohols, add after 0.8mL triethylamine, then add compound-5 (2.51g, 0.005mol) that obtain in embodiment 1, room temperature reaction 24 hours, evaporated under reduced pressure solvent, purification by silica gel column chromatography obtains sterling (2.26g, 72%).
1H?NMR(400MHz，CDCl
3)δ7.94(br.s，1H)，6.54(dd，1H)，5.75(d，1H)，5.33(d，1H)，5.31(d，1H)，3.65(s，2H)，3.23-3.24(m，1H)，3.19(s，2H)，2.95(t，4H)，2.80(t，4H)，2.08-2.32(m，4H)，1.67-1.89(m，6H)，1.62-1.65(m，4H)，1.58(s，6H)，1.42-1.46(m，2H)，1.31-1.34(m，2H)，1.24(s，3H)，0.88(d，3H)，0.66(d，3H)；LC-MS?m/z＝630[M+H]
+。
Embodiment 3:2-(1-(2-amino-3,4-dioxo cyclobutene-1-yl) piperidines-3-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, it is tabular compound 13 that 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester
the preparation of step 1:N-tertbutyloxycarbonyl-3-hydroxy piperidine methanesulfonates
By N-tertbutyloxycarbonyl-3-hydroxy piperidine (2.01g, 0.01mol) be dissolved in 50 milliliters of methylene dichloride, add 0.02 mole of triethylamine, ice-water bath is cooled to 0 DEG C, slowly drip methane sulfonyl chloride (1.37g, 0.012mol), dropwise 0 DEG C of stirring reaction of rear maintenance 2 hours to raw material and disappear, at 0 DEG C, drip 10 milliliters of saturated aqueous ammonium chloride cancellation reactions.Separating funnel separates dichloromethane layer, and 10 milliliters of dichloromethane extractions 2 times for water layer merge organic layer.Organic phase is with after 10 milliliters of washings of saturated aqueous common salt, and Magnesium Chloride Anhydrous is dry, filters, and is spin-dried for solvent and obtains N-tertbutyloxycarbonyl-3-hydroxy piperidine methanesulfonates crude product, is directly used in next step reaction (2.2g, 79%).
1H?NMR(400MHz，CDCl
3)δ4.65-4.73(m，1H)，3.32-3.44(m，4H)，3.02(s，3H)，1.63-1.69(m，2H)，1.47-1.53(m，2H)，1.38(s，9H)；LC-MSm/z＝280[M+H]
+。
step 2:2-(1-N-tertiary butyloxycarbonyl phenylpiperidines-3-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl
base-6-vinyl-3a, 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester
By the methanesulfonates (2.79g obtaining in step 1, 0.01mol) be dissolved in 40 milliliters of dry DMF, in stirring, add raw material-2 (3.94g, 0.01mol), room temperature reaction 12 hours, add 50 ml water cancellation reactions, then use dichloromethane extraction (50 milliliters × 3), organic layer is dry with Magnesium Chloride Anhydrous, filter, be spin-dried for solvent and obtain crude product, anhydrous diethyl ether recrystallization, obtain compound 2-(1-N-tertiary butyloxycarbonyl phenylpiperidines-3-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5, 8-dihydroxyl-4, 6, 9, 10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester sterling (3.86g, 67%).
1H?NMR(400MHz，CDCl
3)δ6.54(dd，1H)，5.75(d，1H)，5.33(d，1H)，5.31(d，1H)，3.67(s，2H)，3.27-3.42(m，6H)，2.07-2.28(m，4H)，1.66-1.71(m，3H)，1.62-1.65(m，2H)，1.61(s，3H)，1.39-1.46(m，16H)，1.29-1.33(m，2H)，1.22(s，3H)，0.86(d，3H)，0.78(d，3H)；LC-MS?m/z＝578[M+H]
+。
step 3:2-(piperidines-3-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl
-3a, 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester hydrochloride
By the compound (5.77g obtaining in step 3,0.01mol) be dissolved in 100 milliliters of anhydrous diethyl ethers, under stirring at room temperature, pass into dry HCl gas, produce gradually white precipitate to not till producing precipitation, filtration under diminished pressure, the vacuum-drying of gained solid, obtains compound 2-(piperidines-3-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester hydrochloride (4.51g, 88%).
1H?NMR(400MHz，CD
3OD)δ6.55(dd，1H)，5.74(d，1H)，5.33(d，1H)，5.31(d，1H)，3.71(s，2H)，3.17-3.26(m，1H)，2.68-2.82(m，4H)，2.11-2.26(m，4H)，1.68-1.71(m，3H)，1.63-1.66(m，2H)，1.61(s，3H)，1.39-1.46(m，7H)，1.29-1.33(m，2H)，1.22(s，3H)，0.88(d，3H)，0.69(d，3H)；LC-MSm/z＝478[M+H]
+。
step 4:2-(1-(2-amino-3,4-dihydro is for cyclobutene-1-yl) piperidines-3-yl) Thiovanic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-bis-
hydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester
By 3-amino-4-oxyethyl group-3-cyclobutene-1 of preparation in embodiment 1,2-diketone (1.41g, 0.01mol) be dissolved in 40 milliliters of dehydrated alcohols, add after 1.0mL triethylamine, then add the hydrochloride (5.13g, 0.01mol) obtaining in step 3, room temperature reaction 36 hours, evaporated under reduced pressure solvent, purification by silica gel column chromatography obtains sterling (4.1g, 71%).
1H?NMR(400MHz，CDCl
3)δ7.99(br.s，2H)，6.53(dd，1H)，5.75(d，1H)，5.34(d，1H)，5.31(d，1H)，3.69(s，2H)，3.22-3.23(m，1H)，2.71-2.82(m，5H)，2.14-2.28(m，4H)，1.69-1.93(m，5H)，1.64-1.67(m，3H)，1.41-1.46(m，7H)，1.30-1.35(m，2H)，1.23(s，3H)，0.86(d，3H)，0.70(d，3H)；LC-MSm/z＝573[M+H]
+。
Embodiment 4:2-((1-(2-amino-3,4-dioxo cyclobutene-1-yl) pyrrolidin-2-yl) methylthio group) acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, it is tabular compound 28 that 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester
the preparation of step 1:N-tertbutyloxycarbonyl-2-hydroxymethyl pyrrolidine methanesulfonates
By N-tertbutyloxycarbonyl-2-hydroxymethyl pyrrolidine (2.01g, 0.01mol) be dissolved in 50 milliliters of methylene dichloride, add 0.02 mole of triethylamine, ice-water bath is cooled to 0 DEG C, slowly drip methane sulfonyl chloride (1.37g, 0.012mol), dropwise 0 DEG C of stirring reaction of rear maintenance 1.5 hours to raw material and disappear, at 0 DEG C, drip 10 milliliters of saturated aqueous ammonium chloride cancellation reactions.Separating funnel separates dichloromethane layer, and 10 milliliters of dichloromethane extractions 2 times for water layer merge organic layer.Organic phase is with after 10 milliliters of washings of saturated aqueous common salt, and Magnesium Chloride Anhydrous is dry, filters, and is spin-dried for solvent and obtains N-tertbutyloxycarbonyl-2-hydroxymethyl pyrrolidine methane sulfonate crude product, is directly used in next step reaction (2.45g, 88%).
1H?NMR(400MHz，CDCl
3)δ4.03-4.08(m，1H)，3.36-3.49(m，3H)，2.99(s，3H)，1.57-1.64(m，2H)，1.43-1.51(m，2H)，1.41(s，9H)；LC-MS?m/z＝280[M+H]
+。
step 2:2-(1-N-tertbutyloxycarbonyl pyrrolidin-2-yl) methylthio group acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-
tetramethyl--6-vinyl-3a 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester
By the methanesulfonates (2.79g obtaining in step 1, 0.01mol) be dissolved in 40 milliliters of dry DMF, in stirring, add raw material-2 (3.94g, 0.01mol), room temperature reaction 9 hours, add 50 ml water cancellation reactions, then use dichloromethane extraction (50 milliliters × 3), organic layer is dry with Magnesium Chloride Anhydrous, filter, be spin-dried for solvent and obtain crude product, anhydrous diethyl ether recrystallization, obtain compound 2-(1-N-tertbutyloxycarbonyl pyrrolidin-2-yl) methylthio group acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5, 8-dihydroxyl-4, 6, 9, 10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester sterling (4.33g, 75%).
1H?NMR(400MHz，CDCl
3)δ6.55(dd，1H)，5.75(d，1H)，5.32(d，1H)，5.30(d，1H)，3.59(s，2H)，3.36-3.52(m，4H)，2.73(dd，2H)，2.09-2.26(m，4H)，1.66-1.71(m，3H)，1.54-1.63(m，7H)，1.41-1.46(m，5H)，1.39(s，9H)，1.28-1.32(m，2H)，1.23(s，3H)，0.85(d，3H)，0.66(d，3H)；LC-MS?m/z＝578[M+H]
+。
step 3:2-(pyrrolidin-2-yl) methylthioglycolic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl
-3a, 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester hydrochloride
By the compound (5.77g obtaining in step 3,0.01mol) be dissolved in 100 milliliters of anhydrous diethyl ethers, under stirring at room temperature, pass into dry HCl gas, produce gradually white precipitate to not till producing precipitation, filtration under diminished pressure, the vacuum-drying of gained solid, obtains compound 2-(pyrrolidin-2-yl) methylthioglycolic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester hydrochloride (4.26g, 83%).
1H?NMR(400MHz，CD
3OD)δ6.48(dd，1H)，5.77(d，1H)，5.34(d，1H)，5.22(d，1H)，3.47(s，2H)，3.21-3.33(m，3H)，2.64(dd，2H)，2.02-2.21(m，4H)，1.66-1.69(m，3H)，1.51-1.59(m，7H)，1.41-1.45(m，5H)，1.26-1.30(m，2H)，1.22(s，3H)，0.87(d，3H)，0.69(d，3H)；LC-MS?m/z＝478[M+H]
+。
step 4:2-((1-(2-amino-3,4-dioxo cyclobutene-1-yl) pyrrolidin-2-yl) methylthio group) acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro
-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester
By 3-amino-4-oxyethyl group-3-cyclobutene-1 of preparation in embodiment 1,2-diketone (1.41g, 0.01mol) be dissolved in 40 milliliters of dehydrated alcohols, add after 1.0mL triethylamine, then add the hydrochloride (5.13g, 0.01mol) obtaining in step 3, room temperature reaction 29 hours, evaporated under reduced pressure solvent, purification by silica gel column chromatography obtains sterling (4.0g, 70%).
1H?NMR(400MHz，CDCl
3)δ8.06(br.s，2H)，6.49(dd，1H)，5.75(d，1H)，5.34(d，1H)，5.27(d，1H)，3.57(s，2H)，3.14-3.21(m，3H)，2.61(dd，2H)，1.97-2.15(m，4H)，1.63-1.87(m，4H)，1.49-1.56(m，7H)，1.39-1.41(m，5H)，1.24-1.29(m，2H)，1.22(s，3H)，0.85(d，3H)，0.74(d，3H)；LC-MS?m/z＝573[M+H]
+。
Embodiment 5:2-((1-(2-amino-3,4-dioxo cyclobutene-1-yl)-4-methylpiperazine-2-yl) methylthio group) acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, it is tabular compound 40 that 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester
the preparation of step 1:1-tertbutyloxycarbonyl-2-methylol-4-methylpiperazine methanesulfonates
By 1-tertbutyloxycarbonyl-2-methylol-4-methylpiperazine (2.3g, 0.01mol) be dissolved in 50 milliliters of methylene dichloride, add 0.02 mole of triethylamine, ice-water bath is cooled to 0 DEG C, slowly drip methane sulfonyl chloride (1.37g, 0.012mol), dropwise 0 DEG C of stirring reaction of rear maintenance 6 hours to raw material and disappear, at 0 DEG C, drip 10 milliliters of saturated aqueous ammonium chloride cancellation reactions.Separating funnel separates dichloromethane layer, and 10 milliliters of dichloromethane extractions 2 times for water layer merge organic layer.Organic phase is with after 10 milliliters of washings of saturated aqueous common salt, and Magnesium Chloride Anhydrous is dry, filters, and is spin-dried for solvent and obtains 1-tertbutyloxycarbonyl-2-methylol-4-methylpiperazine methanesulfonates crude product, is directly used in next step reaction (2.80g, 91%).
1H?NMR(400MHz，CDCl
3)δ3.95(dd，2H)，3.63-3.69(m，1H)，3.13-3.19(m，2H)，2.97(s，3H)，2.57-2.64(m，4H)，2.36(s，3H)，1.39(s，9H)；LC-MS?m/z＝309[M+H]
+。
step 2:2-(1-tertbutyloxycarbonyl-4-methylpiperazine-2-yl) methylthio group acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl
-4,6,9,10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester
By the methanesulfonates (3.08g obtaining in step 1, 0.01mol) be dissolved in 50 milliliters of dry DMF, in stirring, add raw material-2 (3.94g, 0.01mol), room temperature reaction 12 hours, add 50 ml water cancellation reactions, then use dichloromethane extraction (50 milliliters × 3), organic layer is dry with Magnesium Chloride Anhydrous, filter, be spin-dried for solvent and obtain crude product, re-crystallizing in ethyl acetate, obtain compound 2-(1-tertbutyloxycarbonyl-4-methylpiperazine-2-yl) methylthio group acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5, 8-dihydroxyl-4, 6, 9, 10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester sterling (4.73g, 78%).
1H?NMR(400MHz，CDCl
3)δ6.36(dd，1H)，5.58(d，1H)，5.34(d，1H)，5.21(d，1H)，3.99-4.02(m，1H)，3.55(s，2H)，3.15-3.22(m，2H)，2.73(dd，2H)，2.57-2.64(m，4H)，2.36(s，3H)，2.09-2.26(m，1H)，1.66-1.71(m，3H)，1.54-1.63(m，7H)，1.41-1.46(m，5H)，1.39(s，9H)，1.28-1.32(m，2H)，1.23(s，3H)，0.85(d，3H)，0.66(d，3H)；LC-MS?m/z＝607[M+H]
+。
step 3:2-(4-methylpiperazine-2-yl) methylthio group acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5,8-dihydroxyl-46910-tetramethyl--6-second
thiazolinyl-3a, 9-propane-3aH-encircles the preparation of penta cyclooctene-1 (4H)-one-8-ester hydrochloride
By the compound (6.06g obtaining in step 3, 0.01mol) be dissolved in 100 milliliters of anhydrous diethyl ethers, under stirring at room temperature, pass into dry HCl gas, produce gradually white precipitate to not till producing precipitation, filtration under diminished pressure, the vacuum-drying of gained solid, obtain compound 2-(4-methylpiperazine-2-yl) methylthio group acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-octahydro-5, 8-dihydroxyl-4, 6, 9, 10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester hydrochloride (4.29g, 79%).
1H?NMR(400MHz，CD
3OD)δ6.52(dd，1H)，5.77(d，1H)，5.34(d，1H)，5.25(d，1H)，4.11-4.13(m，1H)，3.59(s，2H)，3.17-3.21(m，2H)，2.82(dd，2H)，2.61-2.66(m，4H)，2.47(s，3H)，2.25-2.31(m，1H)，1.69-1.72(m，5H)，1.57-1.64(m，6H)，1.40-1.49(m，5H)，1.27-1.30(m，2H)，1.26(s，3H)，0.81(d，3H)，0.69(d，3H)；LC-MS?m/z＝507[M+H]
+。
step 4:2-((1-(2-amino-3,4-dioxo cyclobutene-1-yl)-4-methylpiperazine-2-yl) methylthio group) acetic acid (3aS, 4R, 5S, 6S, 8R, 9R, 9aR, 10R)-
octahydro-5,8-dihydroxyl-4,6,9,10-tetramethyl--6-vinyl-3a, 9-propane-3aH-encircles penta cyclooctene-1 (4H)-one-8-ester
By 3-amino-4-oxyethyl group-3-cyclobutene-1 of preparation in embodiment 1,2-diketone (1.41g, 0.01mol) be dissolved in 60 milliliters of dehydrated alcohols, add after 1.0mL triethylamine, then add the hydrochloride (5.42g, 0.01mol) obtaining in step 3, room temperature reaction 48 hours, evaporated under reduced pressure solvent, purification by silica gel column chromatography obtains sterling (3.67g, 61%).
1H?NMR(400MHz，CDCl
3)δ7.85(br.s，2H)，6.50(dd，1H)，5.75(d，1H)，5.33(d，1H)，5.29(d，1H)，4.16-4.18(m，1H)，3.48(s，2H)，3.05-3.11(m，2H)，2.79(dd，2H)，2.62-2.65(m，5H)，2.57(s，3H)，2.29-2.32(m，1H)，1.71-1.82(m，4H)，1.61-1.65(m，5H)，1.43-1.48(m，5H)，1.27-1.31(m，2H)，1.24(s，3H)，0.79(d，3H)，0.67(d，3H)；LC-MS?m/z＝602[M+H]
+。
The Antibacterial Activity of compound prepared by the present invention
For objective, scientifically evaluate the In Vitro Bacteriostasis effect of compound sample provided by the invention to 3 kinds of pathogenic bacterium, adopt micro-doubling dilution to measure these samples to the golden bacterium ATCC29213 of Portugal, the minimal inhibitory concentration (MIC) of strangles suis CVCC562 and intestinal bacteria ATCC25922.Test result shows that sample provided by the invention has extraordinary bacteriostatic activity.In following table, sample shows commercially available antibiotic---the fungistatic effect of Tiamulin that is better than or quite contrasts test; Especially sample 11,26,37 and 69 change into after sodium salt solubleness in water is all greater than 100mg/mL, and this provides huge improvement space for follow-up preparation research and bioavailability study.
Table 1: the anti-microbial activity of the compounds of this invention to reference culture
Claims (13)
1. the compound shown in general formula (I), its pharmacy acceptable salt,
Wherein, R
1, R
4, R
5independently represent respectively hydrogen atom, C
1-6alkyl; R
2, R
3independently represent respectively hydrogen atom, carboxyl; B represents OR
6, SR
7or NR
8r
9; Wherein R
6, R
7, R
8, R
9independently represent respectively hydrogen atom, the C being replaced by 0～1 substituting group W
1-6alkyl, described substituting group W is independently selected from hydroxyl, amino, carboxyl, guanidine radicals, C
1-6alkoxyl group, C
1-6alkylthio ,-NHR
10,-NR
11r
12; Wherein substituent R
10, R
11, R
12independently be selected from respectively C
1-6alkyl.
2. compound according to claim 1, its pharmacy acceptable salt, its structural formula is as shown in (II):
Wherein, R
1, represent hydrogen atom, C
1-6alkyl.
3. compound according to claim 1, its pharmacy acceptable salt, its structural formula is as shown in (VI):
Wherein, R
1, represent hydrogen atom, C
1-6alkyl; M representation carboxy.
4. compound according to claim 1, its pharmacy acceptable salt, its structural formula is as shown in (V):
Wherein Q is selected from O, S, NR
13; Wherein R
13represent hydrogen atom, C
1-6alkyl.
5. compound according to claim 1, its pharmacy acceptable salt, its structural formula is as shown in (III):
6. compound according to claim 1, its pharmacy acceptable salt, its structural formula is as shown in (IV):
7. following compounds, its pharmacy acceptable salt, the structure of described compound is:
8. a pharmaceutical composition, by the arbitrary described compound of claim 1-7, its pharmacy acceptable salt, with one or more pharmaceutical carriers and/or thinner composition.
9. pharmaceutical composition according to claim 8, is characterized in that containing the arbitrary described compound of 0.01～10g claim 1-7, its pharmacy acceptable salt, and compound and pharmacy acceptable salt thereof are as essential activeconstituents.
10. the arbitrary described compound of claim 1-7, the application of its pharmacy acceptable salt in the antibacterials of preparation, treatment or prevention animal.
11. application according to claim 10, wherein indication animal is the mankind or other Mammalss or poultry.
12. application according to claim 11, wherein other Mammalss are ox, Ma Heyang.
The preparation method of the arbitrary described compound of 13. claim 1-7, comprises the steps: that (1) provides compound
(2) react and obtain by following formula
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| CN104447450B (en) * | 2014-07-08 | 2016-09-28 | 南通大学 | Cysteine amide-type pleuromutilin derivative and preparation method and medical usage |
| CN104961666B (en) * | 2014-07-08 | 2017-04-12 | 南通大学 | 2-mercaptoacetamide pleuromutilin derivatives, and preparation method and medical application thereof |
| CN115443131A (en) | 2020-04-17 | 2022-12-06 | 纳布里瓦治疗有限责任公司 | Therapeutic use of pleuromutilins |
| WO2021209173A1 (en) | 2020-04-17 | 2021-10-21 | Nabriva Therapeutics GmbH | Novel therapeutic use of pleuromutilins |
| WO2021209596A1 (en) | 2020-04-17 | 2021-10-21 | Nabriva Therapeutics GmbH | Therapeutic use of pleuromutilins |
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