CN106432058A - Preparation method of Niraparib intermediate 4-(3S-piperidine-3-yl)aniline - Google Patents
Preparation method of Niraparib intermediate 4-(3S-piperidine-3-yl)aniline Download PDFInfo
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- CN106432058A CN106432058A CN201610826080.5A CN201610826080A CN106432058A CN 106432058 A CN106432058 A CN 106432058A CN 201610826080 A CN201610826080 A CN 201610826080A CN 106432058 A CN106432058 A CN 106432058A
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- 0 *c1ccc([C@](CC2)CC2=NO)cc1 Chemical compound *c1ccc([C@](CC2)CC2=NO)cc1 0.000 description 2
- SRIPGAMWWVZJSE-GFCCVEGCSA-N CC(C)(C)OC(Nc1ccc([C@@H](CN2)C=CC2=O)cc1)=O Chemical compound CC(C)(C)OC(Nc1ccc([C@@H](CN2)C=CC2=O)cc1)=O SRIPGAMWWVZJSE-GFCCVEGCSA-N 0.000 description 1
- IEUPQMIWWXQXQJ-GFCCVEGCSA-N CC(C)(C)OC(Nc1ccc([C@H](CC2)CC2=O)cc1)=O Chemical compound CC(C)(C)OC(Nc1ccc([C@H](CC2)CC2=O)cc1)=O IEUPQMIWWXQXQJ-GFCCVEGCSA-N 0.000 description 1
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a preparation method of a Niraparib intermediate 4-(3S-piperidine-3-yl)aniline. The preparation method is characterized by comprising the following steps: 1) carrying out a contact reaction on a compound shown as a formula I and hydroxylamine hydrochloride to obtain a compound shown as a formula II; 2) carrying out a catalytic reaction on the compound shown as the formula II in the presence of phenyl dichlorophosphate to obtain a compound shown as a formula III; 3) carrying out a reduction reaction on the compound shown as the formula III to obtain the Niraparib intermediate 4-(3S-piperidine-3-yl)aniline shown as a formula X. A specific reaction process is shown in the description. By adopting the method provided by the invention, the utilization of a metal catalyst and transaminase with a high price is avoided, so that the production cost is lower, and a target product has high yield and stereoselectivity.
Description
Technical field
The invention belongs to pharmaceutical synthesis field, is related to a kind of anticarcinogen Niraparib intermediate 4- (3S- piperidines -3- base)
The preparation method of aniline.
Background technology
It is a kind of oral Poly ADP-ribose polymerase (PARP) inhibitor that Buddhist nun draws Pabuk (Niraparib), can suppress cell
Reparation to DNA damage, its chemical entitled 2- [4- ((3S) -3- piperidyl) phenyl] -2H- indazole -7- Methanamide.Buddhist nun draws Pabuk
Developed by MSD Corp., after transfer Tesaro company, be currently in three phase clinical stages, exploitation indication be ovarian cancer,
Breast carcinoma, carcinoma of prostate etc., clinic tests prove that, the compound is for above-mentioned disease, as follows with good chemical structure
Shown in formula (1)：
For the cancerous cell with BRCA gene mutation, if PARP activity is suppressed further, these cells
A large amount of DNA damage will be produced during division, cause cancer cell death.And normal cell is present because of also BRCA, without PARP
Still can DNA plerosis, simply effect is weaker, but can survive.Here it is PARP inhibitor is used as targeted drug, selectivity is killed
The reason for dead BRCA mutated cancer cells.Niraparib is respectively 3.8nM/ as high activity PARP1/PARP2 inhibitor, IC50
2.1nM, has activity well in BRCA-1 and BRCA-2 mutant tumours cell, compares PARP3, VV-PARP Tank1.
Therefore there is good DEVELOPMENT PROSPECT.
Wallace et al. is in Organic Process Research＆Development (2011,15,831-840)
A kind of method that Buddhist nun draws Pabuk is disclosed, the method is coupled with 3- pyridine boronic acid and to nitro iodobenzene as raw material by suzuki,
Hydro-reduction, tartaric acid splits and obtains key intermediate 4- (3S- piperidines -3- base) aniline, then the intermediate and ortho-nitrophenyl
Benzaldehyde compound reaction, cyclization etc. finally obtain Buddhist nun and draw Pabuk.In the method, intermediate 4- (3S- piperidines -3- base) aniline is received
Rate is extremely low, and cost is extremely high, greatly limit the application of the method.Wherein first step suzuki be coupled used in price
Pyridine -3- boric acid, and product must carry out separating by column chromatography, and hydro-reduction employs expensive Pt reagent,
Increased use cost；Because hydro-reduction does not have three-dimensional selective power, it is necessary to split through tartaric acid, document report
Road through repeatedly split only 20% or so yield, obtain the ee value of 80-90%.Intermediate 4- (3S- piperidines -3- base)
The synthetic route of aniline is as follows：
Jones et al. pharmaceutical chemistry periodical (Journal of Medicinal Chemistry 2009,52 (22),
7170～7185) also there is similar report, it is low as a result similarly to there is yield, split undesirable, poor selectivity.
Therefore, this area needs that a kind of yield of research and development is higher, the more preferable Buddhist nun of selectivity draws Pabuk and its intermediate 4- (3S- badly
Piperidines -3- base) aniline preparation method.
Content of the invention
It is an object of the invention to provide the preparation of a kind of new Niraparib intermediate 4- (3S- piperidines -3- base) aniline
Method, the method overcomes the defects such as yield in existing method is low, poor selectivity and reaction cost are high, process is loaded down with trivial details.
The present inventor has found under study for action, (S)-(-) under the catalysis of-dinaphthol phosphate ester, the benzene of Boc protection
The alkylation that amine can obtain High level of stereoselectivity selection in phenyl 4- position with 2- cyclopentenone obtains Ketocyclopentane base Boc aniline,
Then by obtaining the ketoxime of particular configuration, then ingenious utilization Beckmann rearrangement obtains valerolactam (2- piperidones chemical combination
Thing), Buddhist nun being obtained finally by reduction draws Pabuk (Niraparib) intermediate 4- (3S- piperidines -3- base) aniline.
To achieve these goals, the present invention provides a kind of Niraparib intermediate 4- (3S- piperidines -3- base) aniline
Preparation method, the preparation method is comprised the following steps：
1) compound shown in Formulas I is obtained the compound shown in Formula II with oxammonium hydrochloride. haptoreaction；
2) compound shown in Formula II is obtained the compound shown in formula III in phenyl dichloro phosphate ester catalytic reaction；
3) compound shown in formula III through reduction reaction obtain Buddhist nun shown in Formula X draw Pabuk intermediate 4- (3S- piperidines-
3- yl) aniline, concrete course of reaction is as follows：
In the present invention, in order to promote the formation of ketoxime, under preferable case, in step 1) in also include add copper acetate.
Step 1) catalytic detailed process can be：Compound shown in Formulas I, copper acetate and oxammonium hydrochloride. are added to 75～
In 85% ethanol water, 2～4h of room temperature reaction.Under preferable case, in step 1) in, compound shown in Formulas I and copper acetate,
The mol ratio of the consumption of oxammonium hydrochloride. is 1：1.2～1.5：1～1.2.Under these conditions, particularly in the presence of copper acetate, formula
Ketoxime compounds shown in II are based on trans.
In the present invention, step 1) ketoxime that generates generates Cyclohexamide, specifically, step 2 by Beckmann rearrangement) connect
Touching the process that reacts can be：Compound shown in Formula II, phenyl dichloro phosphate ester are added to 1～2h of back flow reaction in acetonitrile
Obtain the compound shown in formula III.Under the reaction condition, the configurational isomerization of trans ketoxime can be avoided, so as to pass through Bake
Graceful rearrangement reaction obtains the target product shown in formula III.
Under preferable case, in step 2) in, the compound shown in Formula II with the mol ratio of phenyl dichloro phosphate ester consumption is
1：0.02～0.2, more preferably 1：0.05～0.1.
In the present invention, for step 3) reduction reaction, can adopt this area routine method carry out, for example permissible
NaBH is used with reference to the method in WO20140889834And BF3THF etherate reacts in ethanol, it is easy to which ground obtains formula
Buddhist nun shown in X draws Pabuk intermediate 4- (3S- piperidines -3- base) aniline.Above-mentioned method of reducing, can be by amine protecting group group (Boc)
While sloughing, 4- (3S- piperidines -3- base) aniline is directly obtained.
The present invention also provides a kind of preparation method of the compound shown in above-mentioned Formulas I, and the method includes：(S)-(-)-connection
Under naphthol phosphoric acid ester catalysis, Boc- aniline and 2- cyclopentenone are reacted, course of reaction is as follows：
The reaction should not be carried out under high temperature, this is because easily producing the configuration selection of ortho-product and product under high temperature
Property too poor, and the response time is long at low temperature, tests reaction in 8 hours and can not still complete.Under preferable case, shown in the Formulas I
The preparation condition of compound include：Reaction temperature is 10～20 DEG C, and it is acetic acid second that the response time is the solvent of 2～3h, reaction
Ester.
In the case of further preferably, 2- cyclopentenone and Boc- aniline, (S)-(-)-dinaphthol phosphate ester consumption mole
Than for 1：1.1～1.2：0.05～0.15.
In the method for the present invention, each step reaction can carry out post processing according to the conventional method of this area, to the product for obtaining
Conventional purification process, such as extraction, recrystallization etc. can be carried out.Various raw materials used in the method for the present invention are all permissible
Prepare from prior art or be commercially available.
Compared with prior art, advantages of the present invention is mainly manifested in：
(1) present invention draws Pabuk intermediate 4- (3S- piperidines -3- base) aniline to open new route of synthesis, step for Buddhist nun
Less, and the use of metallic catalyst in course of reaction, zest and activating agent such as trimethyl iodine bisulfide etc. is avoided,
More conducively large-scale production.
(2) present invention, avoiding using expensive transaminase, greatly reduce 4- (3S- piperidines -3- base) aniline
Production cost.
(3) preparation method of 4- (3S- piperidines -3- base) aniline of the present invention has good yield and three-dimensional selection
Property.
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.
Preparation example 1
The preparation of the compound shown in Formulas I
By (S)-(-)-dinaphthol phosphoesterase 30 .35g (1mmol) add ethyl acetate in, then successively by Boc- aniline
2.32g (12mmol), 2- cyclopentenone 0.82g (10mmol) are added 10～20 DEG C in above-mentioned ethyl acetate, the response time be 2～
3h, concentrates, is poured in water, then ether extraction, concentrates, petroleum ether recrystallization, and vacuum drying obtains the compound shown in Formulas I
2.58g, yield 93.7%, ee value 99.21%, course of reaction is as follows：
Preparation example 2
The preparation of the compound shown in Formulas I
By (S)-(-)-dinaphthol phosphate ester 5.2g (15mmol) add ethyl acetate in, then successively by Boc- aniline
21.3g (110mmol), 2- cyclopentenone 8.2g (100mmol) are added 10～20 DEG C in above-mentioned ethyl acetate, and the response time is 2
～3h, concentrates, is poured in water, then ether extraction, concentrates, petroleum ether recrystallization, and vacuum drying obtains the compound shown in Formulas I
25.9g, yield 94.2%, ee value 99.41%.
Preparation example 3
The preparation of the compound shown in Formulas I
By (S)-(-)-dinaphthol phosphoesterase 30 .17g (0.5mmol) add ethyl acetate in, then successively by Boc- aniline
2.13g (11mmol), 2- cyclopentenone 0.82g (10mmol) are added 10～20 DEG C in above-mentioned ethyl acetate, the response time be 2～
3h, concentrates, is poured in water, then ether extraction, concentrates, petroleum ether recrystallization, and vacuum drying obtains the compound shown in Formulas I
2.55g, yield 92.6%, ee value 99.17%.
Preparation example 4
Method such as in preparation example 1, except that, using the AlCl of same molar3Replacement (S)-(-)-dinaphthol
Phosphate ester, vacuum drying obtains yellow solid 1.89g, measures para-position product 26.7%, ortho-product 63.2%.
Embodiment 1
The preparation of the compound shown in Formula II
By the compound 2.75g (10mmol) shown in Formulas I, copper acetate 2.7g (15mmol) and oxammonium hydrochloride. 0.76g
(11mmol) it is added in 75% ethanol water of 20ml, room temperature reaction 2h, reaction terminates, ethyl acetate is extracted, saturated common salt
Water washing, organic faciess are concentrated, and Diethyl ether recrystallization obtains compound 2.42g shown in Formula II, yield 95.2%.
Embodiment 2
The preparation of the compound shown in Formula II
By the compound 2.75g (10mmol) shown in Formulas I, copper acetate 2.2g (12mmol) and oxammonium hydrochloride. 0.76g
(11mmol) it is added in 85% ethanol water of 20ml, room temperature reaction 4h, ethyl acetate is extracted, saturated common salt water washing has
Machine is mutually concentrated, Diethyl ether recrystallization, obtains compound 2.39g shown in Formula II, yield 93.9%.
Embodiment 3
The preparation of the compound shown in Formula II
By the compound 2.75g (10mmol) shown in Formulas I, copper acetate 2.4g (13mmol) and oxammonium hydrochloride. 0.83g
(12mmol) it is added in 75% ethanol water of 20ml, room temperature reaction 2h, ethyl acetate is extracted, saturated common salt water washing has
Machine is mutually concentrated, Diethyl ether recrystallization, obtains compound 2.42g shown in Formula II, yield 95.4%.
Embodiment 4
The preparation of the compound shown in formula III
Compound 2.9g (10mmol) shown in Formula II, phenyl dichloro phosphate ester 0.11g (0.5mmol) are added to 10ml
1～2h of back flow reaction in acetonitrile, is cooled to room temperature, and reactant liquor is poured in water, and ethyl acetate is extracted, and saturated common salt water washing has
Machine is mutually concentrated, petroleum ether recrystallization, obtains compound 2.79g shown in formula III, yield 96.1%.
Embodiment 5
The preparation of the compound shown in formula III
Compound 2.9g (10mmol) shown in Formula II, phenyl dichloro phosphate ester 0.17g (0.8mmol) are added to 10ml
1～2h of back flow reaction in acetonitrile, is cooled to room temperature, and reactant liquor is poured in water, and ethyl acetate is extracted, and saturated common salt water washing has
Machine is mutually concentrated, petroleum ether recrystallization, obtains compound 2.73g shown in formula III, yield 94.2%.
Embodiment 6
The preparation of the compound shown in formula III
Compound 2.9g (10mmol) shown in Formula II, phenyl dichloro phosphate ester 0.21g (1mmol) are added to 12ml second
1～2h of back flow reaction in nitrile, is cooled to room temperature, and reactant liquor is poured in water, and ethyl acetate is extracted, and saturated common salt water washing is organic
Mutually concentrate, petroleum ether recrystallization, obtain compound 2.78g shown in formula III, yield 95.7%.
Embodiment 7
The preparation of the compound shown in formula III
Compound 2.9g (10mmol) shown in Formula II, phenyl dichloro phosphate ester 0.04g (0.2mmol) are added to 10ml
1～2h of back flow reaction in acetonitrile, is cooled to room temperature, and reactant liquor is poured in water, and ethyl acetate is extracted, and saturated common salt water washing has
Machine is mutually concentrated, petroleum ether recrystallization, obtains compound 2.55g shown in formula III, yield 88.1%.
Embodiment 8
Buddhist nun draws Pabuk intermediate 4- (3S- piperidines -3- base) aniline
Compound 2.9g (10mmol) shown in formula III is dissolved in THF and is cooled to 5 DEG C, is subsequently adding NaBH4, slowly
Instill ethanol (in 20min).Then BF is instilled in 1h3THF is kept for 2 DEG C continue reaction 1h.Reactant liquor is warmed to room temperature naturally,
HPLC monitoring reaction is completed.Reactant liquor is cooled to 5 DEG C of ＜, and methanol is quenched and adds HCl, then heats to 45 DEG C, stirring reaction
Decompose to B- complex, LC is monitored.Reaction is completed, and reactant liquor cools down and use propyl acetate and water mixed solution dilution, and pH is adjusted to
8, organic faciess are separated, is added water, adjust pH to 10.5.Separate organic faciess again and saturated common salt water washing is used, concentrate, oil recrystallization
Obtain the Buddhist nun shown in Formula X and draw Pabuk intermediate 4- (3S- piperidines -3- base) aniline 1.65g, yield 93.8%.
Claims (8)
1. a kind of preparation method of Niraparib intermediate 4- (3S- piperidines -3- base) aniline, it is characterised in that the preparation method
Comprise the following steps：
1) compound shown in Formulas I is obtained the compound shown in Formula II with oxammonium hydrochloride. haptoreaction；
2) compound shown in Formula II is obtained the compound shown in formula III in phenyl dichloro phosphate ester catalytic reaction；
3) compound shown in formula III obtains the Buddhist nun shown in Formula X through reduction reaction and draws Pabuk intermediate 4- (3S- piperidines -3-
Base) aniline, concrete course of reaction is as follows：
2. preparation method as claimed in claim 1, it is characterised in that in step 1) in also include to add copper acetate, step 1)
Catalytic detailed process is：Compound shown in Formulas I, copper acetate and oxammonium hydrochloride. are added to 75～85% ethanol waters
In solution, 2～4h of room temperature reaction.
3. preparation method as claimed in claim 1, it is characterised in that in step 1) in, the compound shown in Formulas I and acetic acid
Copper, the mol ratio of the consumption of oxammonium hydrochloride. are 1：1.2～1.5：1～1.2.
4. the preparation method described in claim 1, it is characterised in that step 2) catalytic detailed process is：By Formula II institute
The compound for showing, phenyl dichloro phosphate ester are added to 1～2h of back flow reaction in acetonitrile and obtain the compound shown in formula III.
5. preparation method as claimed in claim 1, it is characterised in that in step 2) in, the compound shown in Formula II and phenyl
The mol ratio of either dichlorophosphate consumption is 1：0.02～0.2, preferably 1：0.05～0.1.
6. the preparation method described in claim 1-3, it is characterised in that the preparation method of the compound shown in the Formulas I includes：
(S)-(-) under-dinaphthol phosphate catalytic, Boc- aniline and 2- cyclopentenone are reacted, course of reaction is as follows：
7. the preparation method described in claim 6, it is characterised in that the preparation condition of the compound shown in the Formulas I includes：Instead
Temperature is answered for 10～20 DEG C, it is ethyl acetate that the response time is the solvent of 2～3h, reaction.
8. preparation method as claimed in claim 6, it is characterised in that 2- cyclopentenone and Boc- aniline, (S)-(-)-dinaphthalene
The mol ratio of phenol phosphate ester consumption is 1：1.1～1.2：0.05～0.15.
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Cited By (4)
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|---|---|---|---|---|
| CN109134351A (en) * | 2018-09-21 | 2019-01-04 | 武汉理工大学 | S-3-(4- aminophenyl) piperidines synthetic method |
| 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 |
| CN109810047A (en) * | 2018-03-02 | 2019-05-28 | 上海博邦医药科技有限公司 | (R) synthetic method of the chiral intermediate of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani |
| CN110483376A (en) * | 2019-09-11 | 2019-11-22 | 陈建江 | A kind of synthetic method of intermediate N phenyl -4- piperidones |
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Cited By (9)
| 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 |
| EP3694836A4 (en) * | 2017-10-13 | 2020-09-02 | Zai Lab (Shanghai) Co., Ltd. | Process for preparing intermediate of anti-tumor drug niraparib and intermediate thereof |
| JP2020536948A (en) * | 2017-10-13 | 2020-12-17 | ザイ ラボ （シャンハイ） カンパニー、リミテッド． | Manufacturing methods and intermediates for synthesizing intermediates for the antitumor drug Nilaparib |
| 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 |
| CN109810047A (en) * | 2018-03-02 | 2019-05-28 | 上海博邦医药科技有限公司 | (R) synthetic method of the chiral intermediate of -3- Phenylpiperidine or/and (S) -3- Phenylpiperidine and Ni Lapani |
| CN109134351A (en) * | 2018-09-21 | 2019-01-04 | 武汉理工大学 | S-3-(4- aminophenyl) piperidines synthetic method |
| CN109134351B (en) * | 2018-09-21 | 2022-03-11 | 武汉理工大学 | Synthesis method of S-3- (4-aminophenyl) piperidine |
| CN110483376A (en) * | 2019-09-11 | 2019-11-22 | 陈建江 | A kind of synthetic method of intermediate N phenyl -4- piperidones |
| CN110483376B (en) * | 2019-09-11 | 2020-11-03 | 山西智创药研科技有限公司 | Synthesis method of intermediate N-phenyl-4-piperidone |
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Application publication date: 20170222 |