CN108997333A - A kind of preparation method of -2 inhibitor ABT-199 of the B cell lymphoma factor - Google Patents
A kind of preparation method of -2 inhibitor ABT-199 of the B cell lymphoma factor Download PDFInfo
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- CN108997333A CN108997333A CN201810727122.9A CN201810727122A CN108997333A CN 108997333 A CN108997333 A CN 108997333A CN 201810727122 A CN201810727122 A CN 201810727122A CN 108997333 A CN108997333 A CN 108997333A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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- A61P35/00—Antineoplastic agents
Abstract
The invention discloses the preparation methods of -2 inhibitor ABT-199 of the B cell lymphoma factor a kind of, belong to pharmaceutical synthesis field.Method includes the following steps: starting material 4- fluorosalicylic acid methyl esters, that is, compound II and 1- tert-butoxycarbonyl-piperazine, that is, compound III replaces under the action of phase transfer catalyst, deprotection obtains compound IV in acid condition afterwards, the key intermediate compound V that compound IV and synthesis obtain obtains intermediate VI through reductive amination process under catalyst (sodium triacetoxy borohydride) effect, the carboxylate direct hydrolysis that intermediate VI and raw material VII, that is, 5- bromo-7-azaindole obtain after replacing is acidified to obtain intermediate VIII, last intermediate VIII and Ⅸ amidation of raw material compound obtain target product compound I.Raw material of the present invention are easy to buy or synthesize, and synthesis step is short, total recovery >=40%, avoids using valuableness or is difficult to the raw material bought, is suitable for industrialized production.
Description
Technical field
The invention belongs to technical field of medicine synthesis, inhibit more particularly to a kind of B cell lymphoma factor -2 (BCL-2)
The preparation method of agent.
Background technique
ABT-199 (venetoclax) has the following structure formula:
Molecular formula C45H50ClN7O7S, molecular weight 868.44, English trade name Venclexta, English drug name
Venetoclax, Chinese drug name ABT-199, Chinese chemical name are 4- [4- [[2- (4- chlorphenyl -4,4- dimethyl -1- hexamethylene
Base -1- base] methyl] -1- piperazinyl]-N- [[3- nitro -4- [[(tetrahydro -2H- pyrans -4- base) methyl] amino] phenyl] sulfonic acid
Base] -2- (1H- pyrroles [2,3-b] pyridine -5- oxygroup) benzamide.
Venclexta is by a breakthrough anticarcinogen of Ai Baiwei (AbbVie) and Roche (Roche) cooperative development.It is
The first B cell lymphoma factor -2 (BCL-2) inhibitor of FDA approval, has harvested 4 indications in the U.S..Venclexta is
A kind of oral B cell lymphoma factor -2 (BCL-2) inhibitor, BCL-2 hair in Apoptosis (apoptosis)
Important function is waved, the apoptosis of some cells (including lymphocyte) can be prevented, and over-express in certain types of cancer, with
The formation of drug resistance is related.Venetoclax is intended to the function of selective depression BCL-2, restores the communication system of cell, allows cancer
Cell self-destruction achievees the purpose that treat tumour.The mono- medicine of venetoclax and combination therapy to treat multiple types leukemia, including
CLL, NHL, diffusivity large B cell lymph cancer (DLBCL), acute myeloid leukaemia (AML) and Huppert's disease (MM).
The document of synthesis Venclexta mainly includes US2014/275540, WO2012/71336, US2010/ at present
305122 (corresponding China Patent No. is CN103153993), WO2016/24230, WO 2011/150016.In several patents
Synthetic method about Venclexta is mainly as follows.General line is too long, a total of 10 step.Change in the starting material of reaction
Object 1 is closed, compound 9 is the raw material for being difficult to buy or synthesize, which is difficult to amplify production.In addition, whole route is always received
Rate is too low (less than 10%), and using the palladium class catalyst to anti-valuableness in compound 3 and the reaction of compound 4, totle drilling cost is opposite
It is higher.Using a large amount of potassium phosphate is arrived in compound 8 and the reaction of compound 9, a large amount of phosphorus can be generated under system acid condition
Acid, it is larger to the pollution of environment.
Summary of the invention
The purpose of the present invention is to provide the synthetic method of synthesis Venclexta a kind of new, a kind of B cell lymphoma because
The preparation method of -2 (BCL-2) inhibitor ABT-199 (venetoclax) of son expects that this method has at least one following side
The advantages of face: synthesis step is short, high income, avoid using severe toxicity and/or expensive reagent, suitable for industrialized production, avoid
Use environment pollutes biggish solvent and/or reaction reagent, and raw material is easy to get or easily prepared etc..The present invention is unexpectedly sent out
It is existing, have the advantages that the method for synthesis step feature of the present invention can obtain at least one above-mentioned aspect.The present invention is based on this hairs
Now it is accomplished.Realize that above-mentioned purpose includes the following steps:
(a) make following formula II and formula III compound:
It reacts under phase transfer catalyst effect, obtains the compound of following formula IV:
X: for halogen
(b) self-control obtains the compound of following formula V:
In acid condition, the compound deamination protecting group of formula IV, with the Formula V compound in step (b) in catalyst
The compound of following formula VI is obtained through reductive amination process under effect:
(c) make the compound 5- bromo-7-azaindole of following formula VII:
Compound with the Formula IV in step (b) replaces in the presence of catalyst in alkali systems and obtains following formula VIII's
Compound:
(d) make the compound of following formula Ⅸ:
Under alkaline condition with the Formula VIII compound in step (c), acyl is carried out under dehydrating agent and catalyst collective effect
Aminating reaction obtains the target product ABT-199 of Formulas I.
Content according to a first aspect of the present invention, wherein the compound of Formula II compound and formula III is anti-in step (a)
The organic solvent that should be used is toluene, tetrahydrofuran (THF), one of DMSO or DMF；
Content according to a first aspect of the present invention, wherein the compound of Formula II compound and formula III is anti-in step (a)
Phase transfer catalyst used in answering is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, preferably tetrabutyl iodine
Change ammonium；
Content according to a first aspect of the present invention, wherein in step (a), the compound of Formula II compound and formula III
Reaction is carried out at 30-100 DEG C.
Content according to a first aspect of the present invention, wherein in step (a), the compound of Formula II compound and formula III
Bronsted acid is added after reaction to be deprotected, Bronsted acid used is selected from hydrochloric acid solution, hydrobromic acid solution or its gas；
Content according to a first aspect of the present invention, wherein reacting the solvent used in step (b) and being selected from toluene, diformazan
Benzene, one of Isosorbide-5-Nitrae-dioxane；
Content according to a first aspect of the present invention, wherein in step (b), the compound of formula IV deamination and the change of Formula V
The catalyst that reduction amination is used in object reaction is closed, the reduction amination catalyst is sodium triacetoxy borohydride；
Content according to a first aspect of the present invention, wherein the temperature that catalyst is added is -30-5 DEG C in step (b).Root
According to the content of first aspect present invention, wherein in step (c), the reacting of Formula VII compound and Formula IV compound uses molten
Agent is selected from toluene, Isosorbide-5-Nitrae-dioxane, DMF, one of DMSO；
Content according to a first aspect of the present invention, wherein Formula VII compound is anti-with Formula IV compound in step (c)
Alkali used in answering is potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide etc., preferably cesium carbonate；
Content according to a first aspect of the present invention, wherein Formula VII compound is anti-with Formula IV compound in step (c)
The catalyst answered is cuprous bromide, cuprous iodide, one of stannous chloride.
Content according to a first aspect of the present invention, wherein the compound and Formula VIII compound of formula Ⅸ exist in step (d)
It reacts at a temperature of 0-40 DEG C；
Content according to a first aspect of the present invention, wherein in step (d), the compound and Formula VIII chemical combination alkaloids of formula Ⅸ
Property under the conditions of it is acylated, selected alkali is triethylamine, and pyridine, ammonium hydroxide is medium, preferably triethylamine.
Content according to a first aspect of the present invention, wherein in step (d), the compound and Formula VIII compound acyl of formula Ⅸ
Change reaction, the dehydrating agent used is 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide (EDCI), dicyclohexylcarbodiimide
(DCC), diisopropylcarbodiimide (DIC)；
Content according to a first aspect of the present invention, wherein in step (d), the compound and Formula VIII compound acyl of formula Ⅸ
Change reaction, the catalyst used is DMAP.
Content according to a first aspect of the present invention, wherein the recrystallization solvent of target product Formulas I is first in step (d)
Alcohol/ethyl acetate system, ethyl alcohol/ethyl acetate system, methanol/acetonitrile system, one of ethanol/acetonitrile system；
Content according to a first aspect of the present invention, wherein the recrystallization temperature of target product Formulas I is 30- in step (d)
80℃。
Formula V compound can be prepared according to the method for US20140275540.
The utility model has the advantages that
The present invention provides a kind of new method for preparing Venclexta, this method can not only shorten linear synthetic route
Reaction step, and used reagent is safer and cheap and easily-available, which employs mild reaction condition and it is simple after
Processing method reduces production cost so that the total recovery of linear synthetic route can be improved, therefore is more suitable for industrialization amplification life
It produces.In particular, the method for the present invention has the advantages that at least one following aspect: synthesis step is short, high income, avoids using severe toxicity
And/or it expensive reagent, is easy to get suitable for industrialized production, raw material or easily prepared etc..It is embodied in:
1) raw material that the present invention uses are to be easy to purchase or homemade raw material, avoid use cost in existing literature
Higher fluorine-containing raw material；
2) present invention is ingenious reacts with compound III, that is, one end amido protecting piperazine with compound II, can avoid piperazine
The drawbacks of piperazine both ends react with compound II respectively avoids the generation of by-product to improve the specificity of reaction；
3) when compound II and compound III reacts, the present invention can on the basis of specificity with phase transfer catalyst
Largely improve the yield of the step；
4) the compounds of this invention IV and compound V reaction is catalyzed with sodium triacetoxy borohydride as reduction amination
Agent, more other reductive amination process effects are much higher, not only can guarantee the generation for effectively avoid by-product of reaction, simultaneously
The yield of this step can be improved；
5) compound Ⅸ and when compound VIII amidation in step d of the present invention, it is same using dehydrating agent and catalyst DMAP
Shi Zuoyong can avoid compound VIII chlorine by-product in conjunction with the amino of compound Ⅸ, largely improve the exclusive of reaction
Property and this step efficiency.
Detailed description of the invention
Fig. 1 is the HPLC map of the ABT-199 in embodiment 1
Fig. 2 is the nuclear magnetic resonance spectroscopy of the ABT-199 in embodiment 1
Fig. 3 is the mass spectrogram of the ABT-199 midbody compound VIII cation in embodiment 1
Fig. 4 is the mass spectrogram of the ABT-199 midbody compound VIII anion in embodiment 1
Fig. 5 is the nuclear magnetic resonance spectroscopy of the ABT-199 midbody compound VIII in embodiment 1
Fig. 6 is the nuclear magnetic resonance spectroscopy of the ABT-199 midbody compound V in embodiment 1
Specific embodiment
Embodiment 1
The synthesis of compound IV
34.2g (0.20mol) compound II, 3.1g (8.4mmol) tetra-tert ammonium iodide is added in 1L reaction flask
(TBAI), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 350mLDMSO.It finishes, system heating
To 100 DEG C of reaction 5h or so, controlled in be cooled to after room temperature that the reaction was continued 10h, HPLC or TLC, raw material fully reacting stops anti-
It answers.300mL ethyl acetate is added into filtrate for filtering, and 1h is stirred at room temperature in 83mL concentrated hydrochloric acid solution, filters, obtains compound IV
Faint yellow solid crude product 47.0g.It is directly used in lower step, HPLC:97.8%, yield: 86.3%.
The synthesis of compound V
The DMF that 33.4g (0.46mol) Non-aqueous processing is crossed, 80mL methylene chloride, system cooling are added in 500mL reaction flask
To -5 DEG C, 64.7g (0.42mol) POCl is added dropwise after temperature is stablized3, drop is complete, is to slowly warm up to 20 DEG C of stirring 1h, system is again
It is cooled to 0 DEG C, the about 41.0g of compound 1 is added into system, while 20mL methylene chloride is added, finishes, is delayed after stirring 30min
Slowly it is warming up to system reflux 6h.System reaction terminates, and system is cooled to after room temperature and is poured slowly into 500mL ice water, stirs
30min.Layering, upper organic layer are extracted with 200mLX3 methylene chloride, merge all organic layers, organic layer saturated salt solution
Washing is evaporated off solvent after organic layer is dry, obtains 54.9g light yellow oil compound 2, be directly used in lower step.Yield:
97.9%.30.0g (0.17mol) compound 2, tetrabutylammonium bromide 56.0g, 30mL acetonitrile are added in 1L reaction flask, room temperature is stirred
25% solution of potassium carbonate 63.9g is added after mixing 10min.It finishes, 28.6g compound 3 is added after 10min is stirred at room temperature.It finishes, body
It is that 30 DEG C are heated under nitrogen protection, room temperature when system is cooling after insulation reaction 12h.300mL toluene and 5% is added into system
Sodium bicarbonate solution 300mL, be layered after stirring 5-10min, organic layer is layered after being washed with 300mL saturated common salt, dry, mistake
Filter, filtrate are concentrated to dryness, and the brown oil 40.5g for obtaining compound V is directly used in lower step, yield: 93.7%.1HNMR
(CDCl3): δ 1.00 (s, 6H), 1.49 (t, J=6.6Hz, 2H), 2.28 (t, J=2.1Hz, 2H), 2.38 (m, 2H), 7.13
(m, 2H), 7.34 (m, 2H), 9.49 (s, 1H).
The synthesis of compound VI
It is added in 1L reaction flask
Compound V30.0g (0.12mol) is added in 2L reaction flask, 240mL toluene solution is added with stirring 40.8g
240mL anhydrous tetrahydro furan is added simultaneously in (0.15mol) compound IV.System is cooled to -30 DEG C after stirring 10min at room temperature,
Sodium triacetoxy borohydride 31.6g (0.15mol) is added portionwise after temperature is stablized.It finishes, 4h, HPLC is stirred at room temperature in system
Or it is controlled in TLC, raw material fully reacting.12.5% saline solution 300g is added into filtrate, is layered after stirring 30min for filtering.On
Layer organic layer is washed with 10% citric acid solution 300gX2, then is washed with the sodium bicarbonate solution of 300g concentration 5%, finally full with 300g
It is washed with salt.Organic layer filters the inorganic salts of precipitation after being cooled to -30 DEG C of heat preservation 30min.It is added after organic layer concentration half
240mL acetonitrile, system are heated to 80 DEG C, refilter after solid dissolved clarification, filtrate slow cooling to insulated and stirred 2-4h after 10 DEG C, this
When system in there are a large amount of solids to be precipitated, filtering, filter cake wash with cold acetonitrile 50mL, obtains refining wet product 66.8g, must after drying
49.5g compound VI, HPLC:99.3%.Yield: 88.0%.The synthesis of compound VIII
Compound Compound VI47.0g (0.10mol) is added in 1L reaction flask, 500gDMF, 24.3g (0.12mol) chemical combination
Object VII, 29.7g (0.16mol) cuprous iodide and 78.2g (0.24mol) cesium carbonate.After system is heated to 60 DEG C of reaction 4-6h
It is controlled in TLC or HPLC, raw material fully reacting.System filtering sequentially adds 500g methylene chloride and 500g saturation food into filtrate
Salt water is layered after stirring 10min, and lower organic layer is washed with saturated salt solution 300gX2, and solvent is evaporated off.500g is added into system
Methanol, while it is 20% sodium hydroxide that 40g weight content, which is added, is warming up to HPLC or TLC hydrolysis after 65 DEG C of stirring 2-3h
Terminate.Stopping reaction, stirs lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, filters after insulated and stirred 1h,
Obtain the faint yellow solid object 48.7g of compound VIII, yield: 82.5%, HPLC:98.9%.
1HNMR (DMSO-d6): δ 0.94 (s, 6H), 1.13t, J=6.2Hz, 2H), 1.98 (s, br, 2H), 2.20 (m,
6H), 2.74 (s, br, 2H), 3.13 (m, 4H), 6.36 (d, J=1.75Hz, 2H), 6.72 (dd, J=8.55,2.4Hz, 1H),
7.06 (m, J=7.65,2H), 7.36 (m, J=7.55,2H), 7.40 (d, J=2.35Hz, 1H), 7.46 (t, J=5.5Hz,
1H), 7.74 (d, J=8.8Hz, 1H), 7.98 (d, J=2.5Hz, 1H), 11.59 (m, 1H), 12.1 (s, 1H) compound I's
Synthesis
Compound IX20.3g (0.064mol) is added in 2L reaction flask, 15.8g (0.13mol) DMAP, 22.7g
(0.11mol) DCC and 500mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 37.5g (0.064mol)
The solution of compound VIII and 23.7g (0.23mol) triethylamine and 80mL methylene chloride is slowly dropped in above-mentioned system, drop
Finish, is controlled in HPLC or TLC after 40 DEG C of stirring 2h, raw material fully reacting.14.1g N, N '-dimethyl second two are added into system
Amine.System is heated to 35 DEG C and continues to stir, and the acetum of 200mL concentration 12% is added after temperature is stablized, stirs 10min
Afterwards, it is layered, organic layer is washed with 5% sodium bicarbonate solution 200mL, then is washed with 5% sodium chloride solution 200mL.Organic layer is dry
Dry, 300mL ethyl acetate is added after solvent is evaporated off in filtering, and methanol solution is added dropwise after being heated to 50 DEG C in system, after system clarification
Start to be cooled to 0-5 DEG C, and insulated and stirred 1h, filter, obtains compound as white solid I about 45.4g, yield after worry biscuit is dry
81.6%, HPLC >=99.0%.(
1HNMR (500MHz, DMSO-d6): δ 0.92 (s, 6H), 1.26 (m, 2H), 1.38 (t, J=12.7Hz, 2H),
1.61 (d, 2H), 1.90 (m, 1H), 1.95 (s, 2H), 2.15 (s, br, 2H), 2.20 (s, 4H), 2.75 (s, br, 2H), 3.07
(s, 4H), 3.26 (m, 4H), 3.84 (dd, 2H), 6.19 (d, J=1.8Hz, 1H), 6.39 (dd, J=1.8,1.9Hz, 1H),
6.67 (dd, J=2.0,1.9Hz, 1H), 7.03 (m, 2H), 7.11 (d, 2H), 7.33 (d, 2H), 7.49 (m, 2H), 7.54 (d, J
=2.3,1H), 7.81 (dd, J=1.7,2.3Hz, 1H), 8.04 (d, J=2.5Hz, 1H), 8.56 (d, J=2.25Hz, 1H),
8.58 (t, 1H), 11.65 (m, 1H)
Embodiment 2
The synthesis of compound IV
34.2g (0.20mol) compound II, 3.4g (10.5mmol) tetra-tert ammonium bromide is added in 1L reaction flask
(TBAB), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 500mLTHF.It finishes, system heating
To 30 DEG C of reaction 5h or so, controlled in be cooled to after room temperature that the reaction was continued 12h, HPLC or TLC, raw material fully reacting stops reaction.
Filtering, be stirred at room temperature it is lower HCl gas is passed through into filtrate, until system in again without solid precipitation.Filtering, obtains compound IV's
Faint yellow solid crude product 44.2g.It is directly used in lower step, HPLC:97.8%, yield: 81.2%.
The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V30.0g (0.12mol) is added in 2L reaction flask, 300mL xylene solution is added with stirring 40.8g
240mL anhydrous tetrahydro furan is added simultaneously in (0.15mol) compound IV.System is cooled to -15 DEG C after 10min is stirred at room temperature, to
Temperature is added portionwise sodium triacetoxy borohydride 31.6g (0.15mol) after stablizing, and system temperature is no more than 5 in adition process
℃.It finishes, system is stirred at room temperature in 4h, HPLC or TLC and controls, raw material fully reacting.12.5% food is added into filtrate for filtering
Salt water 300g is layered after stirring 30min.Upper organic layer is washed with 10% citric acid solution 300gX2, then with 300g concentration 5%
Sodium bicarbonate solution is washed, and is finally washed with 300g saturated common salt.Organic layer filters precipitation after being cooled to -30 DEG C of heat preservation 30min
Inorganic salts.240mL acetonitrile is added after half is concentrated in organic layer, and system is heated to 80 DEG C, refilters after solid dissolved clarification, filtrate is slow
Insulated and stirred 2-4h after being cooled to 10 DEG C has a large amount of solids to be precipitated at this time in system, filtering, filter cake is washed with cold acetonitrile 50mL
It washs, obtains purification wet product 60.1g, 43.8g compound VI, HPLC:99.2% are obtained after drying.Yield: 80.4%.
The synthesis of compound VIII
Compound VI47.0g (0.10mol) is added in 1L reaction flask, 600g Isosorbide-5-Nitrae-dioxane, 24.3g (0.12mol)
Compound VII, 23.0g (0.16mol) cuprous bromide and 33.2g (0.24mol) potassium carbonate.After system is heated to 60 DEG C of reaction 6h
It is controlled in TLC or HPLC, raw material fully reacting.System filtering sequentially adds 500g methylene chloride and 500g saturation food into filtrate
Salt water is layered after stirring 10min, and lower organic layer is washed with saturated salt solution 300gX2, and solvent is evaporated off.500g is added into system
Methanol, while the sodium hydroxide that 40g weight content is 20% is added, HPLC or TLC hydrolysis is anti-after being warming up to 65 DEG C of stirring 2-3h
It should terminate.Stop reaction, stir lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, mistake after insulated and stirred 1h
Filter, obtains the faint yellow solid object 44.3g of compound VIII, yield: 75.2%, HPLC:98.3%.The synthesis of compound I
Compound IX20.3g (0.064mol) is added in 2L reaction flask, 15.8g (0.13mol) DMAP, 20.9g
(0.1lmol) EDCI and 500mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 37.5g
The solution of (0.064mol) compound VIII and 23.7g (0.23mol) triethylamine and 200mL methylene chloride is slowly dropped to above-mentioned
In system, drop finishes, and controls in HPLC or TLC after 20 DEG C of stirring 3h, raw material fully reacting.14.1gN, N '-diformazan are added into system
Base ethylenediamine.System is heated to 35 DEG C and continues to stir, and the acetum of 200mL concentration 12%, stirring are added after temperature is stablized
After 10min, layering, organic layer is washed with 5% sodium bicarbonate solution 200mL, then is washed with 5% sodium chloride solution 200mL.It is organic
Layer dries, filters, and 200mL acetonitrile is added after solvent is evaporated off, and methanol solution is added dropwise after being heated to 30 DEG C in system, after system clarification
Start to be cooled to 0-5 DEG C, and insulated and stirred 1h, filter, obtains compound as white solid I about 50.8g, yield after worry biscuit is dry
91.4%, HPLC >=99.0%.
Embodiment 3
The synthesis of compound IV
34.2g (0.20mol) compound II, 2.9g (10.5mmol) tetra-tert ammonium chloride is added in 1L reaction flask
(TBAC), 30.4g (0.22mol) potassium carbonate and 41.0g (0.22mol) compound III and 500mL toluene.It finishes, system heating
To 80 DEG C of reaction 5h or so, controlled in be cooled to after room temperature that the reaction was continued 10h, HPLC or TLC, raw material fully reacting stops reaction.
Filtering, filtrate decompression are spin-dried for.Into system be added 200mL tetrahydrofuran, be stirred at room temperature it is lower HBr gas is passed through into filtrate, directly
It is precipitated again without solid into system.Filtering, obtains the yellow solid crude product 49.2g of compound IV.It is directly used in lower step, HPLC:
97.6%, yield: 77.9%.The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V30.0g (0.12mol) is added in 2L reaction flask, 300mL1,4- dioxane solution is added with stirring
240mL anhydrous tetrahydro furan is added simultaneously in 47.4g (0.15mol) compound IV.System is cooled to 0 after 10rmin is stirred at room temperature
DEG C, it is added portionwise sodium triacetoxy borohydride 31.6g (0.15mol) after temperature is stablized, system temperature is not in adition process
More than 5 DEG C.It finishes, system is stirred at room temperature in 4h, HPLC or TLC and controls, raw material fully reacting.Filtering, is added into filtrate
12.5% saline solution 300g is layered after stirring 30min.Upper organic layer is washed with 10% citric acid solution 300gX2, then is used
The sodium bicarbonate solution of 300g concentration 5% is washed, and is finally washed with 300g saturated common salt.Organic layer is cooled to -30 DEG C of heat preservation 30min
The inorganic salts of precipitation are filtered afterwards.240mL acetonitrile is added after half is concentrated in organic layer, and system is heated to 80 DEG C, after solid dissolved clarification again
Filtering, filtrate slow cooling to insulated and stirred 2-4h after 10 DEG C have a large amount of solids to be precipitated at this time in system, filtering, and filter cake is with cold
Acetonitrile 50mL washing, obtain purification wet product 63.5g, after drying 45.4g compound VI, HPLC:99.0%.Yield:
80.8%.
The synthesis of compound VIII
Compound VI47.0g (0.10mol) is added in 2L reaction flask, 800g toluene, 24.3g (0.12mol) compound
VII, 15.8g (0.16mol) stannous chloride and 7.2g (0.18mol) sodium hydroxide.System be heated to after 40 DEG C of reaction 5h TLC or
It is controlled in HPLC, raw material fully reacting.System filtering, 500g saturated salt solution is added into filtrate, is layered after stirring 10min, on
Layer organic layer is washed with saturated salt solution 300gX2, and solvent is evaporated off.500g methanol is added into system, while 40g weight is added and contains
The sodium hydroxide that amount is 20%, HPLC or TLC hydrolysis terminates after being warming up to 65 DEG C of stirring 2-3h.Stop reaction, under stirring
Acetum tune pH to 5-6 is added dropwise, system is gradually cooled to 0 DEG C, filters after insulated and stirred 1h, obtains the yellowish of compound VIII
Color solids 42.6g, yield: 72.3%, HPLC:97.9%.
The synthesis of compound I
Compound IX20.3g (0.064mol) is added in 2L reaction flask, 15.8g (0.13mol) DMAP, 13.9g
(0.11mol) DIC and 500mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 37.5g (0.064mol)
The solution of compound VIII and 23.7g (0.23mol) triethylamine and 200mL methylene chloride is slowly dropped in above-mentioned system, drop
Finish, is controlled in HPLC or TLC after 0 DEG C of stirring 6h, raw material fully reacting.14.1gN, N '-dimethyl-ethylenediamine are added into system.
System is heated to 35 DEG C and continues to stir, and the acetum of 200mL concentration 12% is added after temperature is stablized, after stirring 10min, point
Layer, organic layer is washed with 5% sodium bicarbonate solution 200mL, then is washed with 5% sodium chloride solution 200mL.Organic layer is dry, mistake
300mL ethyl acetate is added after solvent is evaporated off in filter, and ethanol solution is added dropwise after being heated to 55 DEG C in system, starts after system clarification
It is cooled to 0-5 DEG C, and insulated and stirred 1h, is filtered, obtains compound as white solid I about 49.7g, yield after worry biscuit is dry
89.5%, HPLC >=99.0%.
Embodiment 4
The synthesis of compound IV
17.0g (0.10mol) compound II, 1.6g (4.2mmol) tetra-tert ammonium iodide is added in 1L reaction flask
(TBAI), 15.2g (0.11mol) potassium carbonate and 20.5g (0.11mol) compound III and 200mLDMF.It finishes, system heating
To 90 DEG C of reaction 3h or so, controlled in be cooled to after room temperature that the reaction was continued 6h, HPLC or TLC, raw material fully reacting stops reaction.
Filtering, 200mL ethyl acetate is added into filtrate, and 1h is stirred at room temperature in 24mL40% hydrobromic acid solution.Filtering, obtains compound
The yellow solid crude product 27.6g of IV.It is directly used in lower step, HPLC:98.0%, yield: 87.1%.
The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V 12.5g (0.05mol) is added in 2L reaction flask, 200mL toluene solution is added with stirring 20.0g
200mL anhydrous tetrahydro furan is added simultaneously in (0.063mol) compound IV.System is cooled to -20 DEG C after stirring 10min at room temperature,
Sodium triacetoxy borohydride 13.4g (0.063mol) is added portionwise after temperature is stablized.It finishing, 4h is stirred at room temperature in system,
It is controlled in HPLC or TLC, raw material fully reacting.12.5% saline solution 150g is added into filtrate for filtering, divides after stirring 30min
Layer.Upper organic layer is washed with 10% citric acid solution 150gX2, then is washed with the sodium bicarbonate solution of 150g concentration 5%, is finally used
The washing of 150g saturated common salt.Organic layer filters the inorganic salts of precipitation after being cooled to -30 DEG C of heat preservation 30min.Half is concentrated in organic layer
150mL acetonitrile is added afterwards, system is heated to 80 DEG C, refilters after solid dissolved clarification, filtrate slow cooling to insulated and stirred after 10 DEG C
2-4h has a large amount of solids to be precipitated at this time in system, filtering, filter cake is washed with cold acetonitrile 50mL, obtains 19.5gization after filter cake drying
Close object VI, HPLC:99.1%.Yield: 83.3%.
The synthesis of compound VIII
Compound VI18.8g (0.04mol) is added in 1L reaction flask, 200gDMSO, 9.5g (0.048mol) compound
VII, 12.2g (0.064mol) cuprous iodide and 31.3g (0.096mol) cesium carbonate.System is heated to TLC after 80 DEG C of reaction 3h
Or it is controlled in HPLC, raw material fully reacting.System filtering, 400g methylene chloride and 200g saturated common salt are sequentially added into filtrate
Water is layered after stirring 10min, and lower organic layer is washed with saturated salt solution 200gX2, and solvent is evaporated off.200g first is added into system
Alcohol, while it is 20% sodium hydroxide that 16g content, which is added, HPLC or TLC hydrolysis terminates after being warming up to 65 DEG C of stirring 2-3h.Stop
It only reacts, stirs lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, filters after insulated and stirred 1h, changed
Close the faint yellow solid object 19.0g of object VIII, yield: 83.0%, HPLC:98.6%.
The synthesis of compound I
Compound IX9.5g (0.03mol) is added in 2L reaction flask, 7.3g (0.06mol) DMAP, 10.5g (0.051mol)
DCC and 250mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 17.1g (0.03mol) compound VIII
It is slowly dropped in above-mentioned system with the solution of 10.9g (0.11mol) triethylamine and 200mL methylene chloride, drop finishes, 0 DEG C of stirring
It is controlled in HPLC or TLC after 6h, raw material fully reacting.6.6gN, N '-dimethyl-ethylenediamine are added into system.System is heated to 35
DEG C continue to stir, the acetum of 94mL concentration 12% is added after temperature is stablized, after stirring 10min, layering, organic layer is used
5% sodium bicarbonate solution 100mL is washed, then is washed with 5% sodium chloride solution 100mL.Organic layer dries, filters, and solvent is evaporated off
100mL acetonitrile is added afterwards, ethanol solution is added dropwise after being heated to 55 DEG C in system, starts to be cooled to 0-5 DEG C after system clarification, and protect
Temperature stirring 1h, filtering, consider biscuit it is dry after obtain compound as white solid I about 21.5g (theoretical yield 26.1g), yield 82.3%,
HPLC >=99.0%.
Embodiment 5
The synthesis of compound IV
17.0g (0.10mol) compound II, 1.7g (5.3mmol) tetra-tert ammonium bromide is added in 1L reaction flask
(TBAB), 15.2g (0.22mol) potassium carbonate and 20.5g (0.11mol) compound III and 300mL toluene.It finishes, system heating
To 30 DEG C of reaction 5h or so, controlled in be cooled to after room temperature that the reaction was continued 12h, HPLC or TLC, raw material fully reacting stops reaction.
Filtering, be stirred at room temperature it is lower HCl gas is passed through into filtrate, until system in again without solid precipitation.Filtering, obtains compound IV's
Faint yellow solid crude product 22.5g.It is directly used in lower step, HPLC:98.3%, yield: 82.5%.
The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V15.0g (0.06mol) is added in 1L reaction flask, 200mL1,4- dioxane is added with stirring 20.4g
120mL anhydrous tetrahydro furan is added simultaneously in (0.075mol) compound IV.System is cooled to -10 DEG C after 10min is stirred at room temperature, to
Temperature is added portionwise sodium triacetoxy borohydride 15.8g (0.075mol) after stablizing, and system temperature is no more than 5 in adition process
℃.It finishes, system is stirred at room temperature in 4h, HPLC or TLC and controls, raw material fully reacting.12.5% food is added into filtrate for filtering
Salt water 150g is layered after stirring 30min.Upper organic layer is washed with 10% citric acid solution 150gX2, then with 150g concentration 5%
Sodium bicarbonate solution is washed, and is finally washed with 150g saturated common salt.Organic layer filters precipitation after being cooled to -30 DEG C of heat preservation 30min
Inorganic salts.120mL acetonitrile is added after half is concentrated in organic layer, and system is heated to 80 DEG C, refilters after solid dissolved clarification, filtrate is slow
Insulated and stirred 2-4h after being cooled to 10 DEG C has a large amount of solids to be precipitated at this time in system, filtering, filter cake is washed with cold acetonitrile 30mL
It washs, obtains purification wet product 39.1g, 23.3g compound VI, HPLC:99.1% are obtained after drying.Yield: 83.0%.
The synthesis of compound VIII
Compound VI18.8g (0.04mol) is added in 1L reaction flask, 250g Isosorbide-5-Nitrae-dioxane, 9.5g (0.048mol)
Compound VII, 12.2g (0.064mol) cuprous iodide and 5.4g (0.096mol) potassium hydroxide.System is heated to 60 DEG C of reactions
It is controlled in TLC or HPLC after 3h, raw material fully reacting.System filtering, 300g methylene chloride is sequentially added into filtrate and 200g is full
And saline solution, it is layered after stirring 10min, lower organic layer is washed with saturated salt solution 200gX2, and solvent is evaporated off.It is added into system
200g methanol, while the sodium hydroxide that 16g weight content is 20% is added, it is warming up to HPLC or TLC water after 65 DEG C of stirring 2-3h
Solution reaction terminates.Stop reaction, stir lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, insulated and stirred 1h
After filter, obtain the faint yellow solid object 18.8g of compound VIII, yield: 82.2%, HPLC:98.1%.The conjunction of compound I
At
Compound IX9.5g (0.03mol) is added in 1L reaction flask, 7.3g (0.06mol) DMAP, 9.8g (0.051mol)
EDCI and 200mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 17.1g (0.03mol) compound
The solution of VIII and 10.9g (0.11mol) triethylamine and 70mL methylene chloride is slowly dropped in above-mentioned system, and drop finishes, and 20 DEG C
It is controlled in HPLC or TLC after stirring 3h, raw material fully reacting.6.6gN, N '-dimethyl-ethylenediamine are added into system.System heating
Continue to stir to 35 DEG C, the acetum of 94mL concentration 12% is added after temperature is stablized, after stirring 10min, layering, organic layer
It is washed with 5% sodium bicarbonate solution 100mL, then is washed with 5% sodium chloride solution 100mL.Organic layer dries, filters, and is evaporated off molten
100mL acetonitrile is added after agent, ethanol solution is added dropwise after being heated to 30 DEG C in system, start to be cooled to 0-5 DEG C after system clarification, and
Insulated and stirred 1h, filtering obtain compound as white solid I about 23.6g, yield 90.5%, HPLC >=99.0% after worry biscuit is dry.
Embodiment 6
The synthesis of compound IV
17.1g (0.10mol) compound II, 1.5g (5.3mmol) tetra-tert ammonium chloride is added in 1L reaction flask
(TBAC), 15.1g (0.11mol) potassium carbonate and 20.5g (0.11mol) compound III and 250mLTHF.It finishes, system heating
To 30 DEG C of reaction 7h or so, controlled in be cooled to after room temperature that the reaction was continued 14h, HPLC or TLC, raw material fully reacting stops reaction.
The lower dropwise addition 42mL concentrated hydrochloric acid solution into filtrate is stirred at room temperature, until being precipitated again without solid in system in filtering.Filtering, is changed
Close the faint yellow solid crude product 23.7g of object IV.It is directly used in lower step, HPLC:97.1%, yield: 87.0%.
The synthesis of compound V is the same as embodiment 1.
The synthesis of compound VI
Compound V15.9g (0.064mol) is added in 1L reaction flask, 200mL tetrahydrofuran solution is added with stirring
120mL anhydrous tetrahydro furan is added simultaneously in 22.0g (0.08mol) compound IV.System is cooled to -8 after 10min is stirred at room temperature
DEG C, it is added portionwise sodium triacetoxy borohydride 17.0g (0.08mol) after temperature is stablized, system temperature is not in adition process
More than 5 DEG C.It finishes, system is stirred at room temperature in 2h, HPLC or TLC and controls, raw material fully reacting.Filtering, is added into filtrate
12.5% saline solution 300g is layered after stirring 30min.Upper organic layer is washed with 10% citric acid solution 200gX2, then is used
The sodium bicarbonate solution of 200g concentration 5% is washed, and is finally washed with 200g saturated common salt.Organic layer is cooled to -30 DEG C of heat preservation 30min
The inorganic salts of precipitation are filtered afterwards.130mL acetonitrile is added after half is concentrated in organic layer, and system is heated to 80 DEG C, after solid dissolved clarification again
Filtering, filtrate slow cooling to insulated and stirred 2-4h after 10 DEG C have a large amount of solids to be precipitated at this time in system, filtering, and filter cake is with cold
Acetonitrile 30mL washing, obtain purification wet product 48.9g, after drying 25.7g compound VI, HPLC:99.1%.Yield:
85.8%.
The synthesis of compound VIII
Compound VI23.5g (0.05mol) is added in 1L reaction flask, 260gDMF, 12.2g (0.06mol) compound VII,
11.5g (0.08mol) cuprous bromide and 12.7g (0.12mol) sodium carbonate.System be heated to after 60 DEG C of reaction 6.5h TLC or
It is controlled in HPLC, raw material fully reacting.System filtering, 250g methylene chloride and 250g saturated salt solution are sequentially added into filtrate,
It is layered after stirring 10min, lower organic layer is washed with saturated salt solution 150gX2, and solvent is evaporated off.250g methanol is added into system,
The sodium hydroxide that 20g weight content is 20% is added simultaneously, is warming up to HPLC or TLC hydrolysis knot after 65 DEG C of stirring 2-3h
Beam.Stop reaction, stir lower dropwise addition acetum tune pH to 5-6, system is gradually cooled to 0 DEG C, filters after insulated and stirred 1h, obtains
To the faint yellow solid object 21.2g of compound VIII, yield: 74.4%, HPLC:98.7%.
The synthesis of compound I
Ⅸ 15.8g of compound (0.05mol) is added in 1L reaction flask, 12.2g (0.1mol) DMAP, 10.7g
(0.085mol) DIC and 250mL methylene chloride (DCM) stirs at 20 DEG C of system.By preprepared 28.6g (0.05mol)
The solution of compound VIII and 18.2g (0.18mol) triethylamine and 100mL methylene chloride is slowly dropped in above-mentioned system, drop
Finish, is controlled in HPLC or TLC after 20 DEG C of stirring 3h, raw material fully reacting.11.0gN, N '-dimethyl-ethylenediamine are added into system.
System is heated to 35 DEG C and continues to stir, and the acetum of 160mL concentration 12% is added after temperature is stablized, after stirring 10min, point
Layer, organic layer is washed with 5% sodium bicarbonate solution 160mL, then is washed with 5% sodium chloride solution mL.Organic layer dries, filters,
240mL ethyl acetate is added after solvent is evaporated off, methanol solution is added dropwise after being heated to 50 DEG C in system, starts to cool down after system clarification
To 0-5 DEG C, and insulated and stirred 1h, filtering, consider biscuit it is dry after obtain compound as white solid I about 39.2g, yield 90.3%,
HPLC >=99.0%.
Claims (10)
1. a kind of preparation method of -2 inhibitor ABT-199 of the B cell lymphoma factor, it is characterised in that: this method includes following
Step:
(a) condensation reaction occurs for Formula II and formula III compound, and finally deprotection obtains formula IV compound in acid condition,
Middle X is chlorine or bromine；
(b) Formula V compound obtains Formula IV compound through reductive amination process with formula IV compound；
(c) Formula VII compound and the generation substitution reaction of Formula IV compound obtain Formula VIII compound；
(d) amidation process occurs for Ⅸ compound of formula and Formula VIII compound, obtains Formulas I target product ABT-199 after recrystallization.
2. preparation method according to claim 1, it is characterised in that: in step (a), Formula II compound and formula III compound
Reaction uses organic solvent, and the organic solvent is toluene, tetrahydrofuran (THF), dimethyl sulfoxide (DMSO) or dimethyl
One of formamide (DMF).
3. preparation method according to claim 1, it is characterised in that: use phase transfer catalyst in step (a), the phase turns
Shifting catalyst is selected from tetrabutylammonium chloride, tetrabutylammonium bromide, one of tetrabutylammonium iodide；And/or Formula II compound with
The reaction of formula III compound is carried out at 30-100 DEG C.
4. preparation method according to claim 1, it is characterised in that: in step (a), the remove-insurance in acid condition
Shield is that Bronsted acid is added to be deprotected, and Bronsted acid used is selected from hydrochloric acid solution, hydrobromic acid solution or its gas.
5. preparation method according to claim 1, it is characterised in that: in step (b), reductive amination process uses solvent, described
Solvent be selected from toluene, dimethylbenzene, one of Isosorbide-5-Nitrae-dioxane.
6. preparation method according to claim 1, it is characterised in that: in step (b), the compound of formula IV compound and Formula V
Reaction uses the catalyst of reduction amination, and the catalyst of the reduction amination is sodium triacetoxy borohydride；And/or it is added and urges
The temperature of agent is -30-5 DEG C.
7. preparation method according to claim 1, it is characterised in that: in step (c), Formula VII compound and Formula IV compound
Reaction uses solvent, and the solvent is selected from toluene, Isosorbide-5-Nitrae-dioxane, DMF, one of DMSO；Formula VII closes object and Formula IV
Closing alkali used in object reaction is potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide, one of potassium hydroxide.
8. preparation method according to claim 1, it is characterised in that: in step (c), Formula VII compound and Formula IV compound are sent out
Raw substitution reaction uses catalyst, and the catalyst is cuprous bromide, cuprous iodide, one of stannous chloride.
9. preparation method according to claim 1, it is characterised in that: in step (d), Ⅸ compound of formula and Formula VIII compound are sent out
Raw amidation process uses catalyst and dehydrating agent, and the dehydrating agent is selected from 1- (3- dimethylamino-propyl) -3- ethyl carbon two
Imines (EDCI), dicyclohexylcarbodiimide (DCC), one of diisopropylcarbodiimide (DIC)；The catalyst is
DMAP；And/or Ⅸ compound of formula and Formula VIII compound 0-40 DEG C at a temperature of react.
10. preparation method according to claim 1, it is characterised in that: in step (d), the recrystallization of Formulas I target product is using molten
Agent is recrystallized, and the solvent is methanol/ethyl acetate system, ethyl alcohol/ethyl acetate system, methanol/acetonitrile system, second
One of alcohol/acetonitrile system；And/or
The recrystallization temperature of target product Formulas I is 30-80 DEG C.
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