CN105399657B - Preparation of Ledipasvir key intermediate - Google Patents
Preparation of Ledipasvir key intermediate Download PDFInfo
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- CN105399657B CN105399657B CN201510682164.1A CN201510682164A CN105399657B CN 105399657 B CN105399657 B CN 105399657B CN 201510682164 A CN201510682164 A CN 201510682164A CN 105399657 B CN105399657 B CN 105399657B
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- 0 *c(cc1N)ccc1NC=O Chemical compound *c(cc1N)ccc1NC=O 0.000 description 2
- IGQKYJHUJBZABF-VIFPVBQESA-N CCC[C@H](C)N(C)C(OC(C)(C)C)=O Chemical compound CCC[C@H](C)N(C)C(OC(C)(C)C)=O IGQKYJHUJBZABF-VIFPVBQESA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to preparation of a key intermediate of ledipasvir, in particular to preparation of (1R,3S,4S) -3- (5-halogeno-1H-benzimidazole-2-yl) -2-azabicyclo [2.2.1] heptane-2-carboxylic acid tert-butyl ester. The method has the advantages of cheap raw materials, large-scale commercial purchase and complete avoidance of generation of disubstituted impurities.
Description
Technical field
The present invention relates to Lei Dipawei key intermediates (1R, 3S, 4S) -3- (5- halos -1H- benzimidazolyl-2 radicals-yl) -2-
The novel preparation method of azabicyclo [2.2.1] heptane -2- carboxylic acid tert-butyl esters.
Background technology
Currently, global pharmaceutical market just shows huge commercial opportunities, market manifestation visible one of this point by listing new drug in the recent period
Spot.The vitality in the field also excites enthusiasm of the enterprise to new drug development, the process optimization of new drug intermediate.Lei Dipawei
(Ledipasvir), predecessor is GS-5885, is a kind of NS5A protease inhibitors developed by Gilid Science Co..Lei Di
Completed for Wei after III clinical trial phases, the fixed dosage for Lei Dipawei/Suo Feibuwei of therapeutic gene type I hepatitis C
The tablet of combination, was included on 2 10th, 2014 by American Pharmacopeia.On October 10th, 2014, combination product thunder enlightening replaced Wei/Suo Fei
Bu Wei obtains U.S. FDA approval, trade name Harvoni.Lei Dipawei is by the inhibitory action to NS5A albumen, so as to block
The duplication of viral RNA.Lei Di replaces six chiral centres of Wei Yongyou, on bridge heterocyclic compound 1,3,4 and spiroheterocyclic 6,
This is by the emphasis in being its synthetic work.Lei Dipawei is the granted medicine available for the full oral treatment regimes of hepatitis C, can
Eliminate to conventional injection interfering effects of drug element（IFN）Demand.Lei Dipawei is the NS5A inhibitor with picomole quantities activity,
It is respectively 50 pmol/L and 9 pmol/L to the EC50 values that HCV genotype 1a and 1b are replicated, and with very
High therapeutic index (＞ 100000 of 50/EC of CC 50), it is to HCV with good selectivity in addition, and it is to other
The EC50 values of RNA or DNA viruses are all higher than 10μmol/ L .In clinical test, chronic hcv patient's single oral dose
100 mg are safety and tolerance, and its plasma elimination half life is 10~14 h.For HCV 1a types, main resistance is dashed forward
Height is Tyr93His, even if being to occur medicament-resistant mutation, the plasma concentration of medicine remains above minimum effective concentration.
Lei Dipawei, Chinese is N- [(2S) -1- [(6S) -6- [5- [the fluoro- 7- of 9,9- bis- [2- [(1S, 2S, 4R) -3-
[(2S) -2- (methoxy the amide groups) -3- methyl isophthalic acids-base of oxo-butyl- 1] -3- azabicyclos [2.2.1] heptyl -2- bases] -3H- benzene
And imidazoles -5- bases] fluorenes -2- bases] -1H- imidazoles -2- bases] -5- azaspiros [2.4] heptyl -5- bases] -3- methyl isophthalic acids-oxo butyl- 2-
Base] methyl carbamate；English language Chemical name: Methyl N-[(2S)-1-[(6S)-6-[5-[9,9-Difluoro-7-[2-
[(1S,2S,4R)-3-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]-3-azabicyclo
[2.2.1]heptan-2-yl]-3H-benzimidazol-5-yl]fluoren-2-yl]-1H-imidazol-2-yl]-5-
Azaspiro [2.4] heptan-5-yl] -3-methyl-1-oxobutan-2-yl] carbamate, CAS numbers are：
1256388-51-8, molecular formula is C49H54F2N8O6, molecular weight is：889.00, its trade name：Harvoni is (with Suo Feibu
Wei Zuhe).Chemical constitution is as follows：
Patent US2013/324496, WO2013/40492, US2013/273005 and document J. Med. Chem.
2014,57,2033-2046 all describes Lei Dipawei study on the synthesis.Based on these patents and document, Lei Dipawei synthesis
Mainly prepared by 3 key intermediates I, II, III condensation, key intermediate I is N- (methoxycarbonyl group)-L- figured silk fabrics
Propylhomoserin, key intermediate II be (6S)-tert-butyl group -6- (5- (the bromo- fluoro-9 H-fluoren -2- bases of 9,9- bis- of 7-) -1H- imidazoles -2- bases) -
5- azaspiros [2.4] heptane -5- carboxylates, key intermediate III be (1R, 3S, 4S) -3- (the bromo- 1H- benzimidazolyl-2 radicals of 5- -
Base) -2- azabicyclos [2.2.1] heptane -2- carboxylic acid tert-butyl esters.Based on compound structure, key intermediate C is due to containing multiple
Chiral centre, and with unique azabicyclo [2.2.1] heptane skeleton, its synthesis is of great interest.In the middle of crucial
Body I, II, III structure are as follows：
Patent US2013/324496, WO2013/40492, US2013/273005 and document J. Med. Chem.
2014,57,2033-2046 gives key intermediate III synthetic method.The method of report is to first pass through the bromo- 1,2- of 4-
Phenylenediamine and (1R, 3S, 4S) -2- (tertbutyloxycarbonyl) -2- azabicyclos [2.2.1] heptane -3- carboxylic acids (IV) are in EDC.HCl/
It is condensed under the conditions of HOBt or HATU, obtains region isomer V and VI mixture, the latter is in HOAc heating conditions or EtOH
Heating condition (tube sealing) ShiShimonoseki imidazole ring obtains key intermediate III.Correlated response formula is as follows：
Although the method for above-mentioned patent and document report can smoothly realize key intermediate III preparation, exist
The defect of several respects.Bromo- 1, the 2- phenylenediamines of 4- first are because with aromatic ring diamine structures, the compound is highly unstable, easily
Producing, pack, transport, feed intake during by the dioxygen oxidation in air, so that substantial amounts of impurity to be brought into follow-up reaction
In, this is also the reason for bromo- 1, the 2- phenylenediamines of current 4- are difficult a large amount of progress commercialization buyings；Secondly as bromo- 1, the 2- benzene of 4-
Diamines contains two exposed amino, therefore can produce in condensation reaction two substitution impurity (VII), and two substitution impurity
It is difficult to remove in last handling process, next step reaction can be directly participated in, so as to have influence on the quality of finished medicines.Two substitution is miscellaneous
The structure of matter is as follows：
The present inventor passes through research experiment, invents a kind of new preparation (1R, 3S, 4S) -3- (5- halo -1H- benzo miaows
Azoles -2- bases) -2- azabicyclos [2.2.1] heptane -2- carboxylic acid tert-butyl esters method.This method not only raw material it is cheap, can be a large amount of
Commercialization buying is carried out, and the generation of two substitution impurity can be avoided completely.
The content of the invention
The present invention has following chemical reaction formula：
Prepare (1R, 3S, 4S) -3- (5- halos -1H- benzimidazolyl-2 radicals-yl) -2- azabicyclos [2.2.1] heptane -2- carboxylics
Tert-butyl acrylate (Formula X IV) with (1R, 3S, 4S) -2- (tertbutyloxycarbonyl) -2- azabicyclos [2.2.1] heptane -3- carboxylic acids (IV) and
4- halo -2- nitroanilines (VIII) or 5- halo -2- nitroanilines (IX) are raw material, the two realized by condensation reaction (1R,
3S, 4S) -3- ((4- halo -2- nitrobenzene) carbamyl) -2- azabicyclos [2.2.1] heptane -2- carboxylic acid tert-butyl esters (X) or
(1R, 3S, 4S) -3- ((5- halo -2- nitrobenzene) carbamyl) -2- azabicyclos [2.2.1] heptane -2- carboxylic acid tert-butyl esters
(XI) preparation；X or XI realizes (1R, 3S, 4S) -3- ((4- halo -2- aminobenzenes) carbamyl) -2- by nitro reduction
Azabicyclo [2.2.1] heptane -2- carboxylic acid tert-butyl esters (XII) or (1R, 3S, 4S) -3- ((5- halo -2- aminobenzenes) amino first
Acyl) -2- azabicyclos [2.2.1] heptane -2- carboxylic acid tert-butyl esters (XIII) synthesis；Last XII or XIII is by closing imidazole ring
Complete (1R, 3S, 4S) -3- (5- halos -1H- benzimidazolyl-2 radicals-yl) -2- azabicyclos [2.2.1] heptane -2- carboxylic acid tert-butyl esters
(XIV) synthesis.
X in Formula VIII, IX, X, XI, XII, XIII, XIV represents Cl, Br;
The condensing agent that first step condensation reaction is used includes EDCI, EDC.HCl, HOBt, HATU, PyBOP, DCC or this
The mixture of a little condensing agents, the solvent of reaction includes THF, CH2Cl2, DMF, the alkali used in course of reaction include TEA, DIPEA,
DMAP, pyridine, N- methylmorpholines etc.；First step condensation reaction can also be by IV in SOCl2, methylchloroformate or chloro-carbonic acid second
Acyl chlorides is made under ester effect, is then achieved in the presence of a base with VIII or IX reactions, the alkali used in course of reaction includes
TEA, DIPEA, DMAP, pyridine etc.；
Second step nitro-reduction reaction uses NH2NH2.H2O/FeCl3Reduction system；
3rd is closed imidazole ring reaction and is carried out using HOAc heating conditions.
Brief description of the drawings
Fig. 1 is the HPLC collection of illustrative plates for the compound (XIV) (X=Br) that embodiment 9 is made；
Fig. 2 is the HPLC collection of illustrative plates for the compound XIV (X=Br) that embodiment 11 is made；
Fig. 3 is the HPLC collection of illustrative plates that compound III is made according to patent document；
Fig. 4 is the LC-Mass collection of illustrative plates that compound III is made according to patent document.
Embodiment：
It can more specifically understand the present invention by the following examples, but it illustrates rather than the limitation present invention
Scope.
Embodiment 1：
The preparation of compound (X) (X=Br):Added in clean four-hole boiling flask IV (10.0g, 0.041mol,
1.0eq) with anhydrous CH2Cl2(50 mL), opens magnetic agitation (nitrogen protection).Add DMAP (20mg, 0.16mmol) and 4-
Bromo- 2- nitroanilines (9.8g, 0.045mol), stir after addition, addition hydroxybenzotriazole (HOBT) (6.1g,
0.045mol) with 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (EDC.HCl)(8.6g,
0.045mol).Stirred after addition, reaction system is cooled to 5 DEG C, be then slowly added into triethylamine (TEA) (10.4g,
0.10mol), reaction temperature is kept to be not higher than 10 DEG C during dropwise addition.20h is stirred at room temperature in reaction solution after completion of dropping.React
Cheng Hou, reaction solution adds H2Reaction is quenched in O (50mL), separates organic phase.Aqueous phase CH2Cl2(3 × 40mL) is extracted；Merge
Organic phase, organic phase is washed using 1M HCl (50mL), saturated aqueous common salt (50mL), is then done using anhydrous sodium sulfate
It is dry.Concentration of being pressurizeed at filtering, 40 DEG C of filtrate is dry, and residue obtains yellow after adding isopropyl acetate recrystallization, product filtration drying
Solid X (X=Br) (12.98g, 72%).
Embodiment 2：
The preparation of compound (X) (X=Cl):Anhydrous CH is added in 250mL three-necked flasks2Cl2(90mL), chloro-carbonic acid
Methyl esters (7.5g, 0.079mol) and IV (18.0g, 0.075mol, 1.0eq).Stirred after adding to dissolved clarification, system slowly drops
Diisopropyl ethyl amine (DIPEA, 10.7g, 0.083mol) is slowly added into after warm to 0 DEG C, system temperature is kept during dropwise addition
Degree is no more than 5 DEG C.4- chloro-2-nitroanilines (14.2g, 0.083mol) CH is slowly added into after completion of dropping2Cl2 (90mL)
Solution, keeps system temperature to be no more than 10 DEG C during dropwise addition, takes 1h.System is warmed to room temperature stirring 3 naturally after completion of dropping
h.Reaction system adds H2O (100mL) and reaction is quenched, and standing separates organic phase, aqueous phase CH2Cl2(3 × 90mL) is extracted.Close
And 1M HCl (100mL) are washed after organic phase, then use saturated common salt water washing, organic phase anhydrous sodium sulfate drying.Filtering,
Being pressurizeed at 40 DEG C of filtrate, concentration is dry, and residue obtains a grease using silica gel column chromatography purifying (petrol ether/ethyl acetate, 2/1)
(24.0g, 81%).
Embodiment 3：
The preparation of compound (XI) (X=Br):DMF (60mL), 5- are sequentially added in there-necked flask clean 200mL
Bromo- 2- nitroanilines (8.4g, 0.039mol), IV (8.5g, 0.035mol, 1.0eq) and N- methylmorpholines (7.8g,
0.078mol) .Reaction system cryosel is water-cooled to addition 2- (7- azos BTA)-N, N, N', N'- tetramethyls after 0 DEG C
Urea hexafluorophosphoric acid ester (HATU, 14.6g, 0.038mol).Then, reaction nature is warmed to room temperature reaction 3h.Reaction system is depressurized
Residue adds H after concentration2O (50mL) and CH2Cl2(50mL).Organic phase is separated, aqueous phase uses CH2Cl2(3 × 50mL) extracts
Take.Merge 1M HCl (30mL) after organic phase to wash, then use saturated common salt water washing, organic phase anhydrous sodium sulfate drying.
Filtering, pressurization concentration is dry at 40 DEG C of filtrate, and residue purifies (petrol ether/ethyl acetate, 5/1, then 2/ using silica gel column chromatography
1) brown solid (10.3g, 67%) is obtained.
Embodiment 4：
The preparation of compound (XI) (X=Cl):CH is sequentially added in there-necked flask clean 500mL2Cl2 (150mL)、
5- chloro-2-nitroanilines (16.0g, 0.093mol), IV (20.4g, 0.085mol, 1.0eq), DMAP (11.4g,
0.093mol) with HOBt (12.6g, 0.093mol).Reaction system cryosel, which is water-cooled to after 0 DEG C, adds the Asia of dicyclohexyl carbon two
The CH of amine (DCC, 14.6g, 0.038mol)2Cl2(50mL) solution (about 1h completion of dropping).After completion of dropping, nature is reacted
It is warmed to room temperature reaction 20h.AcOH (10mL) and H are added to reaction system2Reaction is quenched in O (100mL) mixed solution.Filter out
The insoluble matter of generation, 40 DEG C of water-baths of filtrate are concentrated under reduced pressure CH2Cl2Filter again afterwards, filtrate adds CH2Cl2 (3×100mL)
Extracted, the organic phase of merging with 5% NaHCO3(3 × 100mL) is washed, and saturated common salt water washing, anhydrous sulphur are then used again
Sour sodium is dried.Be filtered to remove at sodium sulphate, 40 DEG C of filtrate pressurization concentration dry, residue purified using silica gel column chromatography (petroleum ether/
Ethyl acetate, 5/1, then 2/1) obtain a grease (19.8g, 59%).
Embodiment 5：
The preparation of compound (XII) (X=Br):Toluene (10ml), isopropyl are sequentially added in there-necked flask clean 100mL
Alcohol (10ml), FeCl3 .6H2O (62mg, catalytic amount), activated carbon (1.0g) and X (X=Br, 10g, 0.023mol,
1.0eq), stirred after adding, be warming up to 65 DEG C.Hydrazine hydrate is slowly added dropwise by dropping funel into reaction system
(2.9g, 0.058mol), dropwise addition process has heating, and 1h is dripped off.60-65 DEG C of stirring reaction 4h of system is kept after completion of dropping.Instead
Rear system should be finished and be naturally cooling to room temperature, the solids such as activated carbon are filtered to remove, filtrate adds H2O (100mL) dilutes, Ran Houyong
CH2Cl2(3 × 100mL) is extracted.The organic phase of merging saturated common salt water washing, anhydrous sodium sulfate drying.It is filtered to remove sulfuric acid
Pressurization concentration is dry at sodium, 40 DEG C of filtrate, residue purified using silica gel column chromatography (methylene chloride/methanol, 25/1, then 15/1)
Obtain a grease (8.0g, 85%).
Embodiment 6：
The preparation of compound (XII) (X=Cl):Toluene (10mL), ethanol are sequentially added in there-necked flask clean 100mL
(10mL)、FeCl3 .6H2O (65mg, catalytic amount), activated carbon (1.0g) and X (X=Cl, 10.0g, 0.025mol,
1.0eq), stirred after adding, be warming up to 65 DEG C.Hydrazine hydrate is slowly added dropwise by dropping funel into reaction system
(3.1g, 0.063mol), dropwise addition process has heating, and 1h is dripped off.60-65 DEG C of stirring reaction 4h of system is kept after completion of dropping.Instead
Rear system should be finished and be naturally cooling to room temperature, the solids such as activated carbon are filtered to remove, filtrate adds H2O (100mL) dilutes, Ran Houyong
CH2Cl2(3 × 100mL) is extracted.The organic phase of merging saturated common salt water washing, anhydrous sodium sulfate drying.It is filtered to remove sulfuric acid
Pressurization concentration is dry at sodium, 40 DEG C of filtrate, residue purified using silica gel column chromatography (methylene chloride/methanol, 25/1, then 15/1)
Obtain a grease (7.1g, 78%).
Embodiment 7：
The preparation of compound (XIII) (X=Br):Toluene (10mL), second are sequentially added in there-necked flask clean 100mL
Alcohol (10mL), FeCl3 .6H2O (58mg, catalytic amount), activated carbon (1.0g) and XI (X=Br, 9.5g, 0.022mol,
1.0eq), stirred after adding, be warming up to 65 DEG C.Hydrazine hydrate is slowly added dropwise by dropping funel into reaction system
(2.7g, 0.054mol), dropwise addition process has heating, and 1h is dripped off.60-65 DEG C of stirring reaction 4h of system is kept after completion of dropping.Instead
Rear system should be finished and be naturally cooling to room temperature, the solids such as activated carbon are filtered to remove, filtrate adds H2O (100mL) dilutes, Ran Houyong
CH2Cl2(3 × 100mL) is extracted.The organic phase of merging saturated common salt water washing, anhydrous sodium sulfate drying.It is filtered to remove sulfuric acid
Pressurization concentration is dry at sodium, 40 DEG C of filtrate, residue purified using silica gel column chromatography (methylene chloride/methanol, 25/1, then 15/1)
Obtain a grease (7.4g, 82%).
Embodiment 8：
The preparation of compound (XIII) (X=Cl):Toluene (10mL), second are sequentially added in there-necked flask clean 100mL
Alcohol (10mL), FeCl3 .6H2O (57mg, catalytic amount), activated carbon (1.0g) and XI (X=Cl, 8.4g, 0.021mol,
1.0eq), stirred after adding, be warming up to 65 DEG C.Hydrazine hydrate is slowly added dropwise by dropping funel into reaction system
(2.6g, 0.053mol), dropwise addition process has heating, and 1h is dripped off.60-65 DEG C of stirring reaction 4h of system is kept after completion of dropping.Instead
Rear system should be finished and be naturally cooling to room temperature, the solids such as activated carbon are filtered to remove, filtrate adds H2O (100mL) dilutes, Ran Houyong
CH2Cl2(3 × 100mL) is extracted.The organic phase of merging saturated common salt water washing, anhydrous sodium sulfate drying.It is filtered to remove sulfuric acid
Pressurization concentration is dry at sodium, 40 DEG C of filtrate, residue purified using silica gel column chromatography (methylene chloride/methanol, 25/1, then 15/1)
Obtain a grease (5.1g, 66%).
Embodiment 9：
The preparation of compound (XIV) (X=Br):Sequentially added in there-necked flask clean 100mL XII (X=Br,
5.8g, 0.014mol, 1.0eq), toluene (20mL), AcOH (1.0g, 0.017mol).Reaction system is warming up to 80 DEG C of guarantors
Room temperature is naturally cooling to after temperature reaction 12h.Isopropyl ether (40mL) is added into reaction bulb, 0 DEG C, body are cooled to after stirring
It is 0 DEG C and is incubated filtering after 24h, obtain yellow solid, solid is eluted with the isopropyl ether (5mL) pre-cooled, obtains light yellow after drying
Solid (3.9g, 71%).
Embodiment 10：
The preparation of compound (XIV) (X=Cl):Sequentially added in there-necked flask clean 100mL XII (X=Cl,
6.5g, 0.018mol, 1.0eq), methyl tertiary butyl ether(MTBE) (40mL), AcOH (5.4g, 0.085mol).Reaction system heats up
Room temperature is naturally cooling to after to back flow reaction 12h.Reaction system is concentrated under reduced pressure removing solvent at a temperature of 50 DEG C, in residue plus
Enter isopropyl ether (50mL), filtered after 0 DEG C, 0 DEG C of insulation 24h of system are cooled to after stirring, obtain yellow solid, solid is with advance
Isopropyl ether (6mL) elution first cooled down, light yellow solid (5.3g, 85%) is obtained after drying.
Embodiment 11：
The preparation of compound (XIV) (X=Br):Sequentially added in there-necked flask clean 100mL XIII (X=Br,
5.0g, 0.012mol, 1.0eq), acetonitrile (30mL), AcOH (7.2g, 0.12mol).Reaction system is warming up to 80 DEG C of guarantors
Room temperature is naturally cooling to after temperature reaction 12h.Reaction system is concentrated under reduced pressure removing solvent at a temperature of 50 DEG C, is added in residue different
Propyl ether (50mL), filters after 0 DEG C, 0 DEG C of insulation 24h of system are cooled to after stirring, obtains yellow solid, solid is used cold in advance
But isopropyl ether (5mL) elution, light yellow solid (4.1g, 87%) is obtained after drying.
Embodiment 12：
The preparation of compound (XIV) (X=Cl):Sequentially added in there-necked flask clean 100mL XIII (X=Cl,
4.5g, 0.013mol, 1.0eq)、Dioxane(30mL)、AcOH (3.9g, 0.065mol) .Reaction system is warming up to 80
Room temperature is naturally cooling to after DEG C insulation reaction 12h.Reaction system is concentrated under reduced pressure removing solvent at a temperature of 50 DEG C, in residue plus
Enter isopropyl ether (45mL), filtered after 0 DEG C, 0 DEG C of insulation 24h of system are cooled to after stirring, obtain yellow solid, solid is with advance
Isopropyl ether (5mL) elution first cooled down, light yellow solid (3.8g, 84%) is obtained after drying.
(operation is based on patent US2013/324496, WO2013/40492, US2013/273005 and text to contrast test
Offer J. Med. Chem. 2014,57,2033-2046)：
The preparation of region isomer V and VI mixture：250mL four-hole boiling flasks addition compound IV (18.2g,
0.075mol, 1.0eq), the bromo- 1,2- phenylenediamines (15.4g, 0.082mol) of 4-, HOBt (11.1g, 0.082mol), N,
N- dimethyl acetamides (70mL) and EDC.HCl (15.8g, 0,082mol).Reaction system is cooled to 10 DEG C after stirring,
4- methyl morpholines (22.8g, 0.23mol) are slowly added into by dropping funel, keep system temperature to be not higher than during dropwise addition
20℃.Then, 20h is stirred at room temperature in reaction system.Methyl tertiary butyl ether(MTBE) (150mL) and H are added in reaction solution2O(300mL),
Organic phase fully is separated after vibration, aqueous phase is extracted with methyl tertiary butyl ether(MTBE) (3 × 100mL).Merge organic phase, it is organic to subtract each other
Pressure concentration, residue is dissolved in isopropyl ether (100mL), and 0-5 DEG C is cooled to after stirring, be slowly added to AcOH (4.9g,
0.082mol), 0-5 DEG C of 2 h of stirring of reacting liquid temperature are kept, yellow solid, the isopropyl ether of yellow solid cooling is filtrated to get
(80ml) and the heptane (80ml) of cooling washing, gained solid vacuum drying obtains yellow solid (20.6g, 67%).
Compound III (consistent with compound XIV structures, X=Br) preparation:100mL three-necked flasks add regional isomerism
Body V and VI mixture (10.0g, 0.024mol, 1.0eq), AcOH (7.2g, 0.12mol) and methyl tertiary butyl ether(MTBE)
(40mL).Reaction system is heated to 60 DEG C or so the h of insulation reaction 18.System is naturally cooling to after room temperature add H2O (40mL) quenches
Go out reaction, subsequent 40 potassium hydroxide for adding 1M adjust pH to neutrality, separate organic phase.Aqueous phase with methyl tertiary butyl ether(MTBE) (3 ×
50mL) extracted.Merge organic phase, organic phase saturated common salt water washing, anhydrous sodium sulfate drying.Filtering, is removed under reduced pressure molten
Isopropyl ether (40mL) is added after agent to stir, and then heats to 60 DEG C of progress heat filterings.Filtrate slow cooling is to 0 DEG C, simultaneously
The h of insulated and stirred 5.Filtering, isopropyl ether (10 mL) washing of gained solid bucket cooling, vacuum drying solid obtains compound III
(7.7g, 82%)。
Compound XIV (X=Br) and press that compound XIV (X=Br) that embodiment 9 is made, embodiment 11 are made
Compound III is made by HPLC progress purity comparisons (see accompanying drawing, accompanying drawing 1 according to patent document：The compound that embodiment 9 is made
(XIV) the HPLC collection of illustrative plates of (X=Br)；Accompanying drawing 2：The HPLC collection of illustrative plates for the compound XIV (X=Br) that embodiment 11 is made；It is attached
Fig. 3：Compound III HPLC collection of illustrative plates is made according to patent document), it can be clearly seen that make compound according to patent document
III has two substitution impurity VII (see accompanying drawing 4) of a content 4% or so at 23.447min.
Claims (2)
1. with the structure as shown in Formula X IIWith structure shown in Formula X IIIAcyl
The preparation method of aminated compounds, it is characterised in that the amides compound of the structure as shown in Formula X II and Formula X III is
By structure represented by a formula XWith structure shown in Formula X ICompound use
NH2NH2.H2O and FeCl3Reduction system carry out respectively nitro reduction prepare, wherein Formula X II, Formula X III, Formula X and Formula X I
X in compound is Cl or Br.
2. as claimed in claim 1 have the structure as shown in Formula X IIWith structure shown in Formula X IIIAmides compound preparation method, it is characterised in that the structure as shown in Formula X and Formula X I
Compound preparation method as described in (I) or (II)：(I) as the structure as shown in Formula VIIIWith shown in Formula IX
StructureCompound be (1R, 3S, 4S) -2- (tertbutyloxycarbonyl) -2- azabicyclos with formula IV compound respectively
[2.2.1] heptane -3- carboxylic acidsCondensation reaction is carried out in the presence of condensing agent, solvent and alkali to prepare, its
X in middle Formula VIII and Formula IX compound is Cl or Br, the condensing agent be EDCI, EDC.HCl, HOBt, HATU, PyBOP,
DCC one of which, described solvent is THF, CH2Cl2, DMF one of which, the alkali be TEA, DIPEA, DMAP, pyrrole
Pyridine, the one of which of N- methylmorpholines；(II) it is (1R, 3S, 4S) -2- (tertbutyloxycarbonyl) -2- azepines by formula IV compound
Bicyclic [2.2.1] heptane -3- carboxylic acidsIn SOCl2, methylchloroformate or ethyl chloroformate effect under prepare acyl
Chlorine, then prepares the acyl chlorides of preparation, the alkali is with Formula VIII compound or the reaction of Formula IX compound in the presence of a base
TEA, DIPEA, DMAP, the one of which of pyridine.
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