CN106432195A - Method for preparing (R)-2-(2-methylpyrrolidine-2-yl)-1H-benzimidazole-4-carboxamide - Google Patents
Method for preparing (R)-2-(2-methylpyrrolidine-2-yl)-1H-benzimidazole-4-carboxamide Download PDFInfo
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Abstract
The invention relates to a method for preparing (R)-2-(2-methylpyrrolidine-2-yl)-1H-benzimidazole-4-carboxamide. The method has the advantages of avoiding of trifluoroacetic acid and other strong acids, simplification of present preparation technologies, pollution reduction, cost reduction, and improvement of the purity and the yield of the above product.
Description
Technical field
The present invention relates to medical material medicine synthesizes and in particular to one kind prepares (R) -2- (2- methylpyrrolidin- 2- yl) -1H- benzene
And the method for imidazoles -4- Methanamide.
Background technology
(R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide, shown in the following formula I of its structural formula, referred to as
For ABT-888,
Shown in its dihydrochloride constituted above formula II.ABT-888 is a kind of new oral Poly adenosine diphosphate-ribose polymerase-1
(PARP) inhibitor, it acts on Ki value during PARP-1 and PARP-2 and is respectively 5.2 and 2.9nmol.ABT-888 presses down
The EC50 of C41 cell processed is 2nmol, shows strong when acting on MX-1 Transplanted tumor model with the combination of other cytotoxin medicaments
Anticancer efficacy.The survival rate of clone gene in pulmonary carcinoma H460 cell can be reduced, and suppress DNA to repair.ABT-888 postpones
The tumour growth of NCI-H460 Transplanted tumor model.ABT-888 suppresses PARP in B16F10 and 9L Transplanted tumor model, thus
Strengthen the active anticancer of temozolomide.ABT-888 and radiation combination can reduce tumor vascular formation.In A375
With press tumor size in Colo829 Transplanted tumor model, Jia 3 respectively and 12.5mg ABT-888 is it can be seen that tumor for every kilogram
Interior more than 95% PARP is suppressed.ABT-888 is carrying out the clinical trial of kinds of tumors, wherein ABT-888 and standard chemotherapeutic
Drug combination treatment triple negative breast cancer and nonsmall-cell lung cancer are in the phase iii clinical trial stage.It is expected to become a treatment
Imitate significant targeting anti-tumor new drug.
Chinese patent application CN101155797A, there is provided the synthetic route of two ABT-888：
1st, with pyrrolidine -1,2- dicarboxylic acids -1- Bian ester, 2- methyl ester be initiation material, through iodomethane on 2 methyl, 2
First ester hydrolysis and the coupling of 2,3- diaminobenzene Methanamide, acetic acid closed loop, hydrogenation removing Bian ester, obtain racemization 2- (2- methyl
Pyrrolidin-2-yl) -1H- h-benzimidazole-4-carboxamide；Split through chiral column after closed loop, then hydrogenate and obtain (R) -2- (2-
Methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide.
(R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide can become salt with HCl further.
2nd, with L-Alanine Bian ester as initiation material, through condensation 1- bromo- 3- chloropropane, BOC protection, closed loop, removing benzyl
Obtain R- (2- methyl isophthalic acid-BOC- pyrrolidine) -2 formic acid, removing BOC, react with benzyl chloroformate again and 2,3- diaminourea
Benzoylamide coupling, acetic acid closed loop, obtain 2- (2- methylpyrrolidin- 2- the yl) -1H- benzimidazole -4- formyl of EE about 97%
Amine.Obtain the product that chiral purity is not less than 99.5% if necessary, centre is also required to chiral column and splits, and to obtain (R) -2-
(2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide.
3rd, Lv Tianxiang etc. exists《The improvement in synthesis of PARP inhibitor veliparb》(Chinese pharmaceutical chemistry magazine volume 23
6 phases) in provide the chiral synthesis techniques of ABT888
But, purity is all undesirable with yield.
Content of the invention
We are studied to the synthesis of ABT-888, surprisingly find：Directly with R- (2- methyl isophthalic acid-BOC- pyrrolidine)
- 2- formic acid is raw material, through coupling with 2,3- diaminobenzene Methanamide, product (the R)-tert-butyl group -2- (2- amino -3- after refining
Formyl carbanilino) -2- methylpyrrolidin- 1- carboxylate (its structure is as shown in formula III) flow back in acetic acid solution 2 little
When more than, or first flowed back 2 hours with 100% glacial acetic acid, then it be 2 little to add the water of 5-95% to flow back in reflux solution again
When more than, process directly obtain (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide.
Using the technique of the present invention, there is significant advantage：
1st, existing process needs secondary batching to react, and needs through processing procedure twice, just can obtain product；This invention simplifies
Production technology is it is only necessary to the reaction that once feeds intake, process obtain product.Due to the simplification of technique, the minimizing of processing procedure,
Yield is greatly improved.
2nd, product purity is high, and conventional technique removes BOC protection group mainly due to using trifluoroacetic acid or hydrochloric acid solution, can make formyl
Amido hydrolyzes, and this not only can produce impurity, also can reduce yield.Using present invention process, use weak acid-acetic acid water
Solution, completes to avoid the hydrolysis of Methanamide so that product purity is all improved with yield, product after refined,
Purity is not less than 99%, and chiral purity is not less than 99.5%.
3rd, pollution, reduces cost are reduced, using present invention process, acetic acid solution can not use seriously polluted with fully recovering
Trifluoroacetic acid, the strong acid such as hydrochloric acid to be sloughing BOC.
4th, eliminate palladium carbon catalysis pressurization in former patent technique to be hydrogenated with to slough the step of the carbobenzoxy protection group on pyrrolidine N
Suddenly.
5th, split without using chiral column, with the obvious advantage.
R- (2- methyl isophthalic acid-BOC- pyrrolidine) -2- formic acid used by this patent can be prepared as follows obtaining：
A, existed with Lv Tianxiang etc.《The improvement in synthesis of PARP inhibitor veliparb》In similar method synthesis of chiral intermediate (R)
- 2- methylpyrrole formic acid -1- t-butyl formate
B, with the method synthetic intermediate of patent CN101155797A
C, similar method synthesising racemation intermediate (2- methyl isophthalic acid-BOC- pyrrolidine) -2- formic acid
Again this patent is synthesized with (R) -2- methylpyrrole formic acid -1- t-butyl formate or 2- methylpyrrole formic acid -1- t-butyl formate
Starting intermediates
Simultaneously it has been found that raceme, or (2- methylpyrrolidin- 2- yl) -1H- benzo miaow that chiral purity is not high
Azoles -4- Methanamide, can be by chiral reagent L- (-)-two pairs of toluyl tartaric acid or L- (-)-di-p-methoxy benzene
Formyl tartaric acid or L- (-)-two pairs of benzoyltartaric acid, using resolving agent ratio (R) -2- (2- methylpyrrolidin- 2-
Base) about 2 times of mol ratios of -1H- h-benzimidazole-4-carboxamide resolving agent, in the alcohols solvents such as methanol become salt, Jing Guoyi
Secondary or more fractionation, Re-boostering test just can obtain qualified (R) -2- (2- methylpyrrolidin- 2- yl) -1H- benzimidazole
- 4- Methanamide.To improve chiral purity using chemical resolution agent or to split and had using the fractionation of chiral pillar or purification can not
The advantage of analogy, for reaching heavy dose of medicine of 200mg particularly with using dosage.
Specific embodiment
Embodiment one prepares (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide using 80% acetic acid
6.0 grams of (R)-tert-butyl group -2- (2- amino -3- formyl carbanilino) -2- methylpyrrolidin- 1- carboxylates
(0.016mol), add 80% acetic acid 60ml, be heated to reflux about 6 hours, detection raw material reaction completes, and vacuum steams molten
Agent, the 30ml that adds water is molten clear, neutralizes PH with aqueous slkali (ammonia or 4N sodium hydroxide) while stirring and is more than 8, separates out
White product, stirs 2 hours about, filters, and filter cake washes with water, and ethyl acetate is washed, vacuum drying, and product 25ml is no
Water methanol refines, and obtains product (R) -2- (2- methylpyrrolidin- 2- yl) 3.1 grams of -1H- h-benzimidazole-4-carboxamide,
HPLC 99.7%, chiral purity 99.8%.Yield 77.5%.
Embodiment two prepares (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide using 90% acetic acid
6.0 grams of (R)-tert-butyl group -2- (2- amino -3- formyl carbanilino) -2- methylpyrrolidin- 1- carboxylates
(0.016mol), add 90% acetic acid 60ml, be heated to reflux about 6 hours, detection raw material reaction completes, and vacuum steams molten
Agent, the 30ml that adds water is molten clear, neutralizes PH with aqueous slkali (ammonia or 4N sodium hydroxide) while stirring and is more than 8, separates out
White product, stirs 2 hours about, filters, and filter cake washes with water, and ethyl acetate is washed, vacuum drying, and product 25ml is no
Water methanol refines, and obtains product (R) -2- (2- methylpyrrolidin- 2- yl) 3.0 grams of -1H- h-benzimidazole-4-carboxamide,
HPLC 99.4%, chiral purity 99.9%.Yield 75.0%.
Embodiment three prepares (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide using 50% acetic acid
6.0 grams of (R)-tert-butyl group -2- (2- amino -3- formyl carbanilino) -2- methylpyrrolidin- 1- carboxylates
(0.016mol), add 50% acetic acid 60ml, be heated to reflux about 8 hours, detection raw material reaction completes, and vacuum steams molten
Agent, the 30ml that adds water is molten clear, neutralizes PH with aqueous slkali (ammonia or 4N sodium hydroxide) while stirring and is more than 8, separates out
White product, stirs 2 hours about, filters, and filter cake washes with water, and ethyl acetate is washed, vacuum drying, and product 20ml is no
Water methanol refines, and obtains product (R) -2- (2- methylpyrrolidin- 2- yl) 2.4 grams of -1H- h-benzimidazole-4-carboxamide,
HPLC99.5%, chiral purity 99.7%.Yield 60.0%.
Example IV prepares (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide using the acetic acid reclaiming
6.0 grams of (R)-tert-butyl group -2- (2- amino -3- formyl carbanilino) -2- methylpyrrolidin- 1- carboxylates
(0.016mol) the about 80% acetic acid 70ml, adding embodiment one to reclaim, is heated to reflux about 6 hours, detects raw material reaction
Complete, vacuum steams solvent, the 30ml that adds water is molten clear, use aqueous slkali (ammonia or 4N sodium hydroxide) to neutralize while stirring
It is more than 8 to PH, separates out white product, stir 2 hours about, filter, filter cake washes with water, and ethyl acetate is washed, vacuum
It is dried, product 25ml absolute methanol refines, and obtains product (R) -2- (2- methylpyrrolidin- 2- yl) -1H- benzimidazole
3.05 grams of -4- Methanamide, HPLC 99.6%, chiral purity 99.8%.Yield 76.2%.
Embodiment five L- (-)-to methyldiphenyl formyl tartaric acid (anhydride) resolving racemic 2- (2- methyl
Pyrrolidin-2-yl) -1H- h-benzimidazole-4-carboxamide
6.0 grams of 2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamides (0.0246mol), add no
Water methanol 80ml, agitating heating dissolve, be cooled to 40 DEG C about, add dissolved with L- (-)-to methyldiphenyl formyl winestone
The 80ml absolute methanol solution of sour (anhydride) 9.6 grams (0.0246mol), separates out white product quickly, stirs 2 hours
Left and right, filters, and filter cake absolute methanol is washed, and filter cake need not be dried, and is added in 60ml water, and stirring is neutralized with alkali,
Start change clear, be more than 9 to PH, then separate out solid product, after stirring 4 hours, sucking filtration, filter cake washing three times, very
Empty dry, obtain product (R) -2- (2- methylpyrrolidin- 2- yl) 2.15 grams of -1H- h-benzimidazole-4-carboxamide, HPLC
99.7%, chiral purity is more than 98.0%.Yield 70.0%.
Embodiment six L- (-)-(R) -2- (2- methyl is purified to methyldiphenyl formyl tartaric acid (anhydride)
Pyrrolidin-2-yl) -1H- h-benzimidazole-4-carboxamide
6.0 gram of 98% (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide (0.0240mol), plus
Enter absolute methanol 80ml, agitating heating dissolves, and is cooled to 40 DEG C about, add dissolved with L- (-)-to methyldiphenyl formyl
The 120ml absolute methanol solution of tartaric acid (anhydride) 18.6 grams (0.0246mol), separates out white product, stirring quickly
2 hours about, filter, filter cake absolute methanol is washed, and filter cake need not be dried, and is added in 90ml water, stirring, use alkali
Neutralize, start to become clear, be more than 9 to PH, then separate out solid product, after stirring 4 hours, sucking filtration, filter cake washing three
Secondary, vacuum drying, obtain product (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide 4.0
Gram, HPLC 99.7%, chiral purity 99.7%.Yield 68.0%.
Embodiment seven L- (-) -2- (2- crassitude is split to methyldiphenyl formyl tartaric acid (anhydride)
- 2- base) -1H- h-benzimidazole-4-carboxamide
6.0 grams of 2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamides (0.0246mol), add anhydrous
Methanol 400ml, agitating heating dissolve, be cooled to 40 DEG C about, add dissolved with L- (-)-to methyldiphenyl formyl tartaric acid
The 80ml absolute methanol solution of (anhydride) 9.6 grams (0.0246mol), separates out white product quickly, is heated to reflux, molten
Clearly, low temperature crystallization 24 hours, filter, and filter cake absolute methanol is washed, and filter cake need not be dried, and is added in 60ml water,
Stirring, is neutralized with alkali, starts to become clear, is more than 9 to PH, then separates out solid product, after stirring 4 hours, sucking filtration,
Filter cake is washed three times, vacuum drying, obtains product (R) -2- (2- methylpyrrolidin- 2- yl) -1H- benzimidazole -4-
1.9 grams of Methanamide, HPLC 99.8%, chiral purity 99.9%.Yield 63.3%.
Embodiment eight L- (-) -2- (2- methylpyrrole is split to methoxy dibenzoyl tartaric acid (anhydride)
Alkane -2- base) -1H- h-benzimidazole-4-carboxamide
6.0 grams of 2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamides (0.0246mol), add no
Water methanol 80ml, agitating heating dissolve, be cooled to 40 DEG C about, add dissolved with L- (-)-to methoxy dibenzoyl wine
The 80ml absolute methanol solution of stone acid (anhydride) 10.30 grams (0.0246mol), separates out white product quickly, stirs 2
About hour, filter, filter cake absolute methanol is washed, and filter cake need not be dried, and is added in 60ml water, stirring, with alkali
With, start to become clear, be more than 9 to PH, then separate out solid product, after stirring 4 hours, sucking filtration, filter cake is washed three times,
Vacuum drying, obtains product (R) -2- (2- methylpyrrolidin- 2- yl) 2.3 grams of -1H- h-benzimidazole-4-carboxamide,
HPLC is more than 99.9%, chiral purity 99.8%.Yield 76.7%.
Embodiment nine L- (-)-dibenzoyl tartaric acid (anhydride) fractionation 2- (2- methylpyrrolidin- 2- yl)
- 1H- h-benzimidazole-4-carboxamide
6.0 grams of 2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamides (0.0246mol), add no
Water methanol 80ml, agitating heating dissolves, and is cooled to 40 DEG C about, add dissolved with L- (-)-dibenzoyl tartaric acid is (anhydrous
Thing) 8.9 (0.0246mol) 80ml absolute methanol solution, quickly separate out white product, stir 2 hours about, mistake
Filter, filter cake absolute methanol is washed, and filter cake need not be dried, and is added in 60ml water, stirring, with alkali neutralization, starts to become clear,
It is more than 9 to PH, then separate out solid product, after stirring 4 hours, sucking filtration, filter cake is washed three times, vacuum drying, obtains
To product (R) -2- (2- methylpyrrolidin- 2- yl) 2.2 grams of -1H- h-benzimidazole-4-carboxamide, HPLC 99.6%,
Chiral purity 99.8%.Yield 73.3%.
Embodiment ten L- (-)-(R) -2- (2- first is purified to methyldiphenyl formyl tartaric acid (anhydride)
Base pyrrolidin-2-yl) -1H- h-benzimidazole-4-carboxamide
6 grams of 2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamides (0.0246mol), detection finds
2- containing 70% ((R) -2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide, adds absolute methanol 80ml,
Agitating heating dissolve, be cooled to 40 DEG C about, add dissolved with L- (-)-to methyldiphenyl formyl tartaric acid (anhydride) 13.5
The 100ml absolute methanol solution of gram (0.0,345mol), separates out white product quickly, stirs 2 hours about, filters,
Filter cake absolute methanol is washed, and filter cake need not be dried, and is added in 80ml water, stirring, with alkali neutralization, starts to become clear, so
Separate out solid product afterwards, after stirring 4 hours, sucking filtration, filter cake is washed three times, vacuum drying, obtains product (R) -2-
(2- methylpyrrolidin- 2- yl) 3.6 grams of -1H- h-benzimidazole-4-carboxamide, HPLC 99.7%, chiral purity 99.8%.
Yield 85.7%.
Embodiment ten one 100% acetic acid adds water preparation (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide
6.0 grams of (R)-tert-butyl group -2- (2- amino -3- formyl carbanilino) -2- methylpyrrolidin- 1- carboxylates
(0.016mol), add 100% acetic acid 60ml, be heated to reflux about 2 hours, detection raw material reaction completes, and add water 12ml,
Backflow 4 hours, vacuum steams solvent, and the 30ml that adds water is molten clear, uses aqueous slkali (ammonia or 4N sodium hydroxide) while stirring
Neutralize PH and be more than 8, separate out white product, stir 2 hours about, filter, filter cake washes with water, and ethyl acetate is washed,
Vacuum drying, product 25ml absolute methanol refines, and obtains product (R) -2- (2- methylpyrrolidin- 2- yl) -1H- benzo
2.5 grams of imidazoles -4- Methanamide, HPLC 99.2%, chiral purity 99.5%.Yield 64.0%.
Claims (4)
1. the method that one kind prepares (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide, it is characterized in that comprising with
Lower step：Intermediate (the R)-tert-butyl group -2- (2- amino -3- formyl carbanilino) -2- methylpyrrolidin- 1- carboxylate is in acetic acid
Flow back in solution and obtain product.
2. preparation method according to claim 1, is characterized in that the concentration range of wherein said acetic acid aqueous solution is 5%～95%, excellent
Select 10%～90%, most preferably 80%；The amount of wherein acetic acid solution is (R)-tert-butyl group -2- (2- amino -3- formyl Carbanilino
Base) -2- methylpyrrolidin- 1- carboxylate：Acetic acid solution=1 gram：2～30 milliliters, preferably 1 gram：5～15 milliliters.
3. the method that one kind prepares (R) -2- (2- methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide, is characterized in that raceme
Or 2- (2- methylpyrrolidin- 2- the yl) -1H- h-benzimidazole-4-carboxamide less than 99.5% for the chiral purity splits through resolving agent
Obtain the product that chiral purity is not less than 99.5%.
4. preparation method according to claim 3, it is characterized in that resolving agent therein be L- (-)-two pairs of toluyl winestones
Acid, L- (-) acid of-di-p-methoxy benzoyltartaric or L- (-)-two pairs of benzoyltartaric acid, resolving agent：2-(R)-(2-
Methylpyrrolidin- 2- yl) -1H- h-benzimidazole-4-carboxamide=1～3mol：1mol, preferably 2mol:1mol；Temperature is 0～100
DEG C, preferably 25～60 DEG C, most preferably 40 DEG C；Solvent is methanol, ethanol, propanol, isopropanol, n-butyl alcohol, isobutanol, tertiary fourth
One of alcohol, water, glycol dimethyl ether, DMF, DMSO, pyridine, preferably methanol.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10556887B2 (en) | 2017-10-24 | 2020-02-11 | Apotex Inc. | Processes for the preparation of Veliparib and intermediates thereof |
| CN111471039A (en) * | 2020-05-20 | 2020-07-31 | 苏州明锐医药科技有限公司 | Preparation method of veliparib |
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| CN101155797A (en) * | 2005-04-11 | 2008-04-02 | 艾博特公司 | 1h-benzimidazole-4-carboxamides substituted with a quaternary carbon at the 2-position are potent parp inhibitors |
| CN102863428A (en) * | 2011-07-09 | 2013-01-09 | 广东东阳光药业有限公司 | Spiro-compounds taken as hepatitis c virus (HCV) inhibitor |
| CN103396405A (en) * | 2013-08-21 | 2013-11-20 | 中国药科大学 | Benzimidazole-4-formamide derivate with PARP (poly-ADP-ribose polymerase) inhibiting effect |
| CN103483322A (en) * | 2013-08-21 | 2014-01-01 | 中国药科大学 | 5-fluoro-1H-benzimidazole-4-formamide derivatives, as well as preparation method and medical application thereof |
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| CN102863428A (en) * | 2011-07-09 | 2013-01-09 | 广东东阳光药业有限公司 | Spiro-compounds taken as hepatitis c virus (HCV) inhibitor |
| CN103396405A (en) * | 2013-08-21 | 2013-11-20 | 中国药科大学 | Benzimidazole-4-formamide derivate with PARP (poly-ADP-ribose polymerase) inhibiting effect |
| CN103483322A (en) * | 2013-08-21 | 2014-01-01 | 中国药科大学 | 5-fluoro-1H-benzimidazole-4-formamide derivatives, as well as preparation method and medical application thereof |
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| 吕天翔等: "PARP抑制剂veliparib的合成工艺改进", 《中药药物化学杂志》 * |
| 徐春秀等: "新型PARP抑制剂veliparib", 《现代药物与临床》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10556887B2 (en) | 2017-10-24 | 2020-02-11 | Apotex Inc. | Processes for the preparation of Veliparib and intermediates thereof |
| CN111471039A (en) * | 2020-05-20 | 2020-07-31 | 苏州明锐医药科技有限公司 | Preparation method of veliparib |
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