CN106432057A - Method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate - Google Patents
Method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate Download PDFInfo
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- CN106432057A CN106432057A CN201610826079.2A CN201610826079A CN106432057A CN 106432057 A CN106432057 A CN 106432057A CN 201610826079 A CN201610826079 A CN 201610826079A CN 106432057 A CN106432057 A CN 106432057A
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- aminophenyl
- piperidines
- butyl formate
- raceme
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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- Organic Chemistry (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a method for preparing (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate. The method is characterized by comprising the following steps: 1) performing a contact reaction on a 3-(4-aminophenyl)-piperidyl-1-tert-butyl formate racemate and (R)-(-)-binaphthyl-2,2-diyl hydrogen phosphate, cooling, crystallizing, and filtering to obtain a solid compound A; (2) hydrolyzing the solid compound A obtained in the step (1) under an acidic condition, adjusting the pH to be 8 to 10 after the hydrolysis reaction is completed, extracting with ethyl acetate, and concentrating to obtain the (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate. The method provided by the invention is high in yield and high in product optical purity, and provides a new way for preparing the (3S)-3-(4-aminophenyl)-piperidyl-1-tert-butyl formate.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to one kind prepares (3S) -3- (4- aminophenyl) piperidines -1- formic acid
The method of the tert-butyl ester.
Background technology
It is a targeted inhibition agent for PARP gene that Buddhist nun draws Pabuk (Niraparib), its chemical entitled 2- [4-
((3S) -3- piperidyl) phenyl] -2H- indazole -7- Methanamide, concrete structure formula is represented by a formula X.Buddhist nun draws Pabuk to be demonstrate,proved by clinic
In fact can be effective to kinds cancer, such as ovarian cancer, breast carcinoma, carcinoma of prostate etc..Buddhist nun draws Pabuk become second listing
PARP inhibitor, with huge potential using value.
PARP is the cutting substrate of apoptosis core member's caspase (caspase).It DNA damage reparation with
Play an important role in apoptosis.If DNA damage cannot be repaired, cell is possible to death.For with BRCA
For the cancerous cell of gene mutation, if PARP activity is suppressed further, a large amount of DNA during these cell divisions, will be produced
Damage, cause cancer cell death.And normal cell is because also BRCA is present, without PARP still can DNA plerosis, simply effect
Weaker, but can survive.Here it is PARP inhibitor is used as targeted drug, selectivity kills the original of BRCA mutated cancer cells
Cause.Buddhist nun draws Pabuk to be exactly based on this mechanisms play inhibitory action and carries out targeted therapy to cancerous cell, while avoiding to normal
The side effect of cell.
Draw preparing for Pabuk unsatisfactory currently for Buddhist nun, main using (3S) -3- (4- aminophenyl) piperidines -1- first
Tert-butyl acrylate is prepared as key intermediate, but by splitting acquisition (3S) -3- (4- aminophenyl) in prior art
The method of piperidines -1- t-butyl formate there are problems of yield low and.
Merck ＆ Co., Inc. Jones et al. is in pharmaceutical chemistry magazine (J Med Chem 2009,52 (22):7170-85) disclose
The preparation method of one kind (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate.The method is with 4- (piperidines -3- base) aniline
For raw material, with ethanol as solvent, L-TARTARIC ACID as resolving agent, split and obtain (S) -4- (piperidines -3- base) aniline, then pass through again
Boc protection obtains (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate, and concrete reaction equation is as follows：
But the method solvent load is big, and crystallization time is long, and yield is only 24% or so afterwards repeatedly to crystallize (three times),
And product ee value is only 80% or so.The method is extremely not suitable for industrialized production.
WO2008084261 discloses the preparation method of one kind (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate,
The method, with 4- (piperidines -3- base) aniline as raw material, is resolving agent through chiral separation system using L- dibenzoyl tartaric acid
For (S) -4- (piperidines -3- base) aniline is obtained, then product is obtained through Boc protection, reaction equation is as follows
But the method needs the resolving agent L- dibenzoyl tartaric acid using 2 times amount, high cost, tear open in the case
Divide yield still extremely low, repeatedly refined rear ee value is also only 80% or so.
Additionally, said method is also present is that Boc2O reacts using optical voidness (S) -4- (piperidines -3- base) aniline for obtaining
During still can with phenyl on amino reaction, cause optics pure products waste, and the by-product be not only difficult to separate and
And the reaction of subsequent intermediates can not be carried out.
Therefore, in view of Buddhist nun draws the good market prospect of Pabuk, this area still needs to a kind of high and fractionation selection of resolution yield
Property good Buddhist nun draw the chemical resolution preparation method of Pabuk intermediate (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate.
Content of the invention
The technical problem to be solved is：A kind of Buddhist nun is provided and draws Pabuk intermediate (3S) -3- (4- aminophenyl)
The chemical resolution preparation method of piperidines -1- t-butyl formate, the method resolution yield is high, optical purity of products height, without the need for special
Equipment, suitable large-scale production, is to prepare highly purified Buddhist nun further to draw Pabuk to provide raw material supply.
To achieve these goals, the invention discloses one kind prepares (3S) -3- (4- aminophenyl) piperidines -1- formic acid uncle
The method of butyl ester, the method is comprised the following steps：
1) by 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme and (R)-(-)-dinaphthol phosphate ester connect
Reaction is touched, cooling crystallization, filters to obtain solid chemical compound A；
2) by step 1) the solid chemical compound A that obtains is hydrolyzed in acid condition, and will reaction after the completion of hydrolysis
Liquid adjusts pH to 8-10, and ethyl acetate is extracted, and concentrates, obtains (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate.
In the present invention, it is preferred in the case of, step 1) detailed process include：By 3- (4- aminophenyl) piperidines -1- first
Tert-butyl acrylate raceme and (R)-(-)-dinaphthol phosphate ester is added in mixed solvent, then heats to 75～85 DEG C of contacts anti-
Answer 1～2 hour, after haptoreaction, continue stirring and 45～50 DEG C of insulations 0.5～1 hour are naturally cooled to, then naturally cool to
Room temperature, is filtrated to get solid chemical compound A, and the mixed solvent is 3～8 by volume ratio：1 DMF is constituted with water.
In order to improve resolution yield, it is further preferred that the mixed solvent is 5～8 by volume ratio:1 DMF and water group
Become.With respect to every g 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme, the consumption of the mixed solvent is 10-
20mL.
In step 1) in, under preferable case, 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme and (R)-(-) -
The molar ratio of dinaphthol phosphate ester is 1：1～1.2.
The present inventor under study for action it has surprisingly been found that, in haptoreaction by add catalytic amount monovalence copper chemical combination
Thing, it is possible to increase (R)-(-) polarity effect of-dinaphthol phosphate ester, promote 3- (4- aminophenyl) piperidines -1- t-butyl formate
Raceme and (R)-(-) combination of-dinaphthol phosphate ester, copper (I) participates in the shape of solid chemical compound A with P and N Atomic coordinate
Become, optical selective and resolution yield is improved, it is therefore preferable that in the case of, step 1) it is additionally included in addition Cu in haptoreaction
(I) compound.Cu (I) compound can be CuCl, CuI or CuBr, preferably CuI.Under preferable case, Cu (I)
Compound is 1 with the molar ratio of 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme：0.2～0.4.
In step 2) in, acid condition causes solid chemical compound A to occur hydrolysis that optics pure products are dissociated, the acidity
Condition should ensure that the abundant of hydrolysis will also be so that t-butyl formate protection group not be removed, it is preferred that the acid condition is referred to
Hydrolysis are carried out in 5～10% acid solutions, and the acid solution is preferably hydrochloric acid solution.After hydrolysis, (R)-(-)-connection
Naphthol phosphoric acid ester also can separate out, can by adjust the method such as pH and extraction be reclaimed.
Preferably, step 2) in the alkali that adjusts used by pH to 8-10 be sodium hydroxide, sodium carbonate or cesium carbonate.
Various raw materials can be obtained by conventional route in the present invention, such as 3- (4- aminophenyl) piperidines -1- formic acid
Tert-butyl ester raceme is commercially available or is prepared by prior art (such as WO2008084261)；(R)-(-)-connection
Naphthol phosphoric acid ester can also be commercially available.
In the present invention, the process of haptoreaction and hydrolysis can be monitored by conventional method, for example
TLC, HPLC, GC etc., haptoreaction or hydrolysis terminate to refer to that in reaction, excess raw material is not remaining less than 0.2%.Ability
(3S) -3- (4- amino that field technique personnel can be obtained to the method for the present invention through methods such as recrystallization according to actual needs
Phenyl) piperidines -1- t-butyl formate carries out conventional purification.
In the present invention, for the effect of the convenient description present invention, by a kind of enantiomer with respect to another kind
The amount of enantiomer is expressed as percent enantiomeric excess, and which is abbreviated as " %ee ".Percent enantiomeric excess can be according to
Following equation is calculated：%ee=[([A]-[B])/([A]+[B])] × 100, wherein [A] is a kind of content of enantiomer, and [B]
Content for another kind of enantiomer.
Compared with prior art, the present invention provides one kind and prepares (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate
New way, simple to operate, reaction is easy to get with raw material, and product yield and ee value are effectively improved.
Specific embodiment
The present invention is further described below by way of specific embodiment, the present invention is not limited only to following examples.At this
In bright scope or without departing from the change in present disclosure, spirit and scope, the present invention being carried out, combination or replacing
Change, will be apparent to the person skilled in the art, and be included within the scope of the present invention.
Embodiment 1
The method that one kind prepares (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate, the method includes following step
Suddenly：
1) by 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme 27.6g (100mmol), (R)-(-)-dinaphthalene
Phenol phosphate ester 38.3g (110mmol), CuI3.8g (20mmol) are added in 150ml mixed solvent, and the mixed solvent is by body
Product is than being 5：1 DMF is constituted with water, then heats to 75 DEG C of haptoreactions 1 hour, after haptoreaction, continues stirring nature cold
But to 50 DEG C be incubated 1 hour, then naturally cool to room temperature, be filtrated to get solid chemical compound A.
2) by step 1) the solid chemical compound A that obtains is hydrolyzed in 10% hydrochloric acid solution of 50ml, and hydrolysis are completed
Add sodium hydroxide that reactant liquor is adjusted pH to 10 afterwards, ethyl acetate is extracted, and is concentrated, petroleum ether recrystallization, and vacuum drying is obtained
(3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate 12.6g, yield 91.3%, HPLC purity (area normalization method)
99.91%, ee value, 99.57% (chiral HPLC (post：Chiralpak AD, 5x50cm；Eluent：10% ethanol/heptane；Pressure
Power：15bar；Flow velocity：35ml/min)).
Embodiment 2
The method that one kind prepares (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate, the method includes following step
Suddenly：
1) by 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme 27.6g (100mmol), (R)-(-)-dinaphthalene
Phenol phosphate ester 41.8g (120mmol), CuI7.6g (40mmol) are added in 150ml mixed solvent, and the mixed solvent is by body
Product is than being 7：1 DMF is constituted with water, then heats to 80 DEG C of haptoreactions 1 hour, after haptoreaction, continues stirring nature cold
But to 45 DEG C be incubated 1 hour, then naturally cool to room temperature, be filtrated to get solid chemical compound A.
2) by step 1) the solid chemical compound A that obtains is hydrolyzed in 60ml5% hydrochloric acid solution, after the completion of hydrolysis
Add sodium hydroxide that reactant liquor is adjusted pH to 9, ethyl acetate is extracted, concentrate, petroleum ether recrystallization, vacuum drying is obtained
(3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate 12.5g, yield 90.6%, HPLC purity (area normalization method)
99.64%, ee value 99.46%.
Embodiment 3
The method that one kind prepares (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate, the method includes following step
Suddenly：
1) by 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme 27.6g (10mmol), (R)-(-)-dinaphthol
Phosphate ester 36.6g (105mmol), CuCl2.8g (30mmol) are added in 180ml mixed solvent, and the mixed solvent is by volume
Than for 8：1 DMF is constituted with water, then heats to 85 DEG C of haptoreactions 1.5 hours, after haptoreaction, continues stirring nature cold
But to 50 DEG C be incubated 0.5 hour, then naturally cool to room temperature, be filtrated to get solid chemical compound A.
2) by step 1) the solid chemical compound A that obtains is hydrolyzed in 50ml10% hydrochloric acid solution, and hydrolysis are completed
Add cesium carbonate that reactant liquor is adjusted pH to 8 afterwards, ethyl acetate is extracted, and is concentrated, petroleum ether recrystallization, and vacuum drying is obtained
(3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate 12.4g, yield 90.2%, HPLC purity (area normalization method)
99.86%, ee value 99.53%.
Embodiment 4
The method that one kind prepares (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate, the method includes following step
Suddenly：
1) by 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme 27.6g (100mmol), (R)-(-)-dinaphthalene
Phenol phosphate ester 38.3g (110mmol), CuI3.8g (20mmol) are added in 150ml mixed solvent, and the mixed solvent is by body
Product is than being 5：1 DMF is constituted with water, then heats to 75 DEG C of haptoreactions 1 hour, then naturally cools to room after haptoreaction
Temperature, is filtrated to get solid chemical compound A.
2) by step 1) the solid chemical compound A that obtains is hydrolyzed in 10% hydrochloric acid solution of 50ml, and hydrolysis are completed
Add sodium hydroxide that reactant liquor is adjusted pH to 10 afterwards, ethyl acetate is extracted, and is concentrated, petroleum ether recrystallization, and vacuum drying is obtained
(3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate 11.4g, yield 82.6%, HPLC purity (area normalization method)
99.25%, ee value, 99.01% (chiral HPLC (post：Chiralpak AD, 5x50cm；Eluent：10% ethanol/heptane；Pressure
Power：15bar；Flow velocity：35ml/min)).
Embodiment 5
As embodiment 1 preparation (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate method, except that,
The mixed solvent is 1 by volume ratio：1 DMF is constituted with water.Vacuum drying obtains (3S) -3- (4- aminophenyl) piperidines -1-
T-butyl formate 11.8g, yield 85.7%, HPLC purity (area normalization method) 99.73%, ee value 99.60%.
Embodiment 6
As embodiment 1 preparation (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate method, except that,
It is added without CuI.It is vacuum dried and (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate 10.3g is obtained, yield 74.4%,
HPLC purity (area normalization method) 99.05%, ee value 98.29%.
Embodiment 7
As embodiment 1 preparation (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate method, except that,
CuI0.95g (5mmol) is added, vacuum drying obtains (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate 11.3g, receives
Rate 82.3%, HPLC purity (area normalization method) 99.33%, ee value 99.07%.
Embodiment 8
As embodiment 1 preparation (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate method, except that,
CuCl using same molar2CuI is substituted, vacuum drying obtains (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate
10.3g, yield 75.2%, HPLC purity (area normalization method) 98.37%, ee value 97.65%.
Embodiment 9
As embodiment 1 preparation (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate method, except that,
Step 2) be hydrolyzed in 25% hydrochloric acid solution reaction, and vacuum drying obtains (3S) -3- (4- aminophenyl) piperidines -1- formic acid
Tert-butyl ester 12.4g, yield 82.2%, HPLC purity (area normalization method) 96.31%, ee value 98.89%, wherein containing de-
Boc product 2.73%.
Comparative example 1
As embodiment 1 preparation (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate method, except that,
Using equivalent weight (S)-(+)-dinaphthol phosphate ester substitute (R)-(-)-dinaphthol phosphate ester, vacuum drying obtain faint yellow
Solid 10.2g, containing (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate 69.82%.
Claims (10)
1. the method that one kind prepares (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate, it is characterised in that the method bag
Include following steps：
1) by 3- (4- aminophenyl) piperidines -1- t-butyl formate raceme and (R)-(-)-dinaphthol phosphate ester carry out contacting anti-
Should, cooling crystallization, filter to obtain solid chemical compound A；
2) by step 1) the solid chemical compound A that obtains is hydrolyzed in acid condition, after the completion of hydrolysis adjusts reactant liquor
Section pH to 8-10, ethyl acetate is extracted, and is concentrated, is obtained (3S) -3- (4- aminophenyl) piperidines -1- t-butyl formate.
2. the method for claim 1, it is characterised in that step 1) detailed process include：By 3- (4- aminophenyl)
Piperidines -1- t-butyl formate raceme and (R)-(-)-dinaphthol phosphate ester is added in mixed solvent, then heat to 75～
85 DEG C of haptoreactions 1～2 hour, after haptoreaction, continue stirring and naturally cool to 45～50 DEG C to be incubated 0.5～1 hour, then
Room temperature is naturally cooled to, solid chemical compound A is filtrated to get, the mixed solvent is 3～8 by volume ratio：1 DMF is constituted with water.
3. method as claimed in claim 2, it is characterised in that the mixed solvent by volume ratio be:1 DMF and water
Composition.
4. method as claimed in claim 1 or 2, it is characterised in that step 1) it is additionally included in haptoreaction and adds Cu (I) to change
Compound.
5. method as claimed in claim 4, it is characterised in that Cu (I) compound be.
6. the method as described in claim 4 or 5, it is characterised in that Cu (I) compound and 3- (4- aminophenyl) piperazine
The molar ratio of pyridine -1- t-butyl formate raceme is 1：0.2～0.4.
7. method as claimed in claim 2 or claim 3, it is characterised in that with respect to every g 3- (4- aminophenyl) piperidines -1- formic acid
Tert-butyl ester raceme, the consumption of the mixed solvent is 10-20mL.
8. method as claimed in claim 1 or 2, it is characterised in that in step 1) in, 3- (4- aminophenyl) piperidines -1- first
Tert-butyl acrylate raceme and (R)-(-) molar ratio of-dinaphthol phosphate ester is 1：1～1.2.
9. method as claimed in claim 5, it is characterised in that step 2) acid condition refer to hydrolysis 5～10%
Carry out in acid solution, the acid solution is hydrochloric acid solution.
10. the method for claim 1, it is characterised in that step 2) in the alkali that adjusts used by pH to 8-10 be hydroxide
Sodium, sodium carbonate or cesium carbonate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019072237A1 (en) | 2017-10-13 | 2019-04-18 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
| US20220041575A1 (en) * | 2017-04-24 | 2022-02-10 | Tesaro, Inc. | Methods of manufacturing of niraparib |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20220041575A1 (en) * | 2017-04-24 | 2022-02-10 | Tesaro, Inc. | Methods of manufacturing of niraparib |
| US11629137B2 (en) * | 2017-04-24 | 2023-04-18 | Tesaro, Inc. | Methods of manufacturing of niraparib |
| WO2019072237A1 (en) | 2017-10-13 | 2019-04-18 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
| US10927077B2 (en) | 2017-10-13 | 2021-02-23 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
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