CN108409604A - The preparation method of Letrozole key intermediate - Google Patents
The preparation method of Letrozole key intermediate Download PDFInfo
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Abstract
The present invention provides a kind of preparation method of Letrozole key intermediate (I), with 2- (4- cyano-phenyls) formic acid (II), 4- halogenated benzonitriles (III) for raw material, under alkali, solvent and catalysts conditions, single step reaction generates target product.The preparation method route is novel, and easy to operate controllable, reaction yield is high, economy, and can ensure that the follow-up Letrozole that high-purity is prepared, and the industrial scale amplification production for the Letrozole of high-purity provides guarantee.
Description
Technical field
The invention belongs to pharmaceutical intermediate preparing technical field, more particularly to a kind of third generation arimedex comes
The synthetic method of bent azoles intermediate.
Background technology
Letrozole (Letrozole), chemical name 4,4 '-(1H-1,2,4- triazole -1- methines)-two benzonitriles are
The highly selective arimedex of the third generation of Novartis Co., Ltd's exploitation is made by inhibiting aromatizing enzyme under estrogen level
Drop, activity in vivo is 150-250 times stronger than first generation arimedex aminoglutethimide, especially suitable for postclimacteric mammary gland
Cancer patient.Since it is selectively higher, glucocorticoid, mineralocorticoid and thyroid function, large dosage use pair are not influenced
Adrenocorticosteroids substance secretes unrestraint effect, therefore has higher therapeutic index.
Jiangxi Normal University's Master's thesis《The synthesising process research of Aromatase Inhibitor Letrozole》Chapter 2, summarized in
Disclosed six main Letrozole synthetic routes before 2014, in conjunction with after 2014 about Letrozole synthetic route
Report, Letrozole synthetic method disclosed in the prior art mainly has：
Route one
Patent US4749713 discloses the synthetic route of Letrozole earliest：, as raw material, to be given birth to through bromination to methyl cyanophenyl
Pairs of bromomethyl cyanophenyl, then with 1H-1, the reaction of 2,4- triazoles generates 4- [1- (1,2,4- triazole) methyl]-cyanophenyl, finally
It is reacted with to fluorobenzonitrile, target product Letrozole is made.The route can also obtain phase other than generating target product Letrozole
1 answered, 3,4- position isomer by-products.
To reduce the generation of by-product, the product after the patents such as CN200410080092.5 react second step carries out
Isomer separation.The amount of hydrochloric acid is added by control, two isomers of control at the sequence being precipitated after salt, and then both detach at
Product after salt, with alkaline hydrolysis from then carrying out three-step reaction.The yield of two steps is 45.1% after the improvement, can effectively improve and
The purity of bent azoles, but the improved method needs to use a certain amount of corrosive strong acid, highly basic, and a large amount of waste water are generated, it is uncomfortable
For industrialized production.
WO2004076409 etc. replaces 1H-1 using 4- amino-1,2,4-triazoles, and 2,4- triazoles improve N- alkyl
The selectivity for changing reaction, obtains second step reaction product using deaminizing, reduces the generation of isomers.But it uses
This improved method gross production rate does not increase, and the diazo-reaction for deaminizing is not suitable for industrialized production.
《Chinese Journal of Pharmaceuticals, 2015,46 (3), 225-227》It discloses and uses 1H-1,2,4- 1-Sodium-1,2,4-Triazoles replace 1H-
The improved method of 1,2,4- triazole.This method improves the yield of rear two step to 54.8%, but there is still a need for use strong acid strong
Alkali, and two-step reaction is required to control and carries out at low temperature, is not suitable for industrialized production equally.
Route two
US4978672 discloses N- tertiary butyls and is reacted with Ethyl formate brombenzamide, raw in the presence of n-BuLi
At 4,4 '-two (N- tertiary butyls amidophenyl) methanol, 4,4 '-dicyano diphenyl methyl chlorides are obtained through chlorination, then with
Target product Letrozole is made in 1H-1, the condensation of 2,4- triazoles.The route needs -60 DEG C of low temperature and organolithium, large-scale production
Of high cost, security risk is big.
Route three
《China Medicine University reports, 2003,34 (4)：375-376》In using aniline as starting material, obtained with formaldehyde condensation
Diazonium salt solution is obtained by the reaction to 4,4 '-diaminodiphenyl-methanes, then with sodium nitrite, after add cuprous cyanide, through weight
4,4 '-dicyano diphenyl methanes are made in nitridation reaction, synthesize 4,4 '-dicyano diphenyl bromomethanes through NBS bromos, finally
With 1H-1, condensation reaction occurs for 2,4- triazole potassium, finally obtained target product Letrozole.The synthetic route is long, and diazotising is anti-
The cuprous cyanide toxicity used in answering is big, and security risk is big, and total recovery only 5.3%, is unsuitable for industrial production.
Route four
The intermediate in route three after three-step reaction has been made by single step reaction by WO2007144896, it is rear using with
Three identical method of route, totally three steps target product Letrozole is made.The route avoids making for toxic reagent cuprous cyanide
With, but first step reaction yield is relatively low, and product separating difficulty is big, total recovery only 10.3%.
Above-mentioned Master's thesis《The synthesising process research of Aromatase Inhibitor Letrozole》The route is improved,
By controlling the research of each response parameter in each step, total recovery is improved to 15.6%, is still unsuitable for industrializing big rule
Mould produces.
Route five
WO2007074474, as raw material, 4 are obtained by the reaction through Friedel-Crafts to methyl benzoyl chloride and toluene,
4 '-dimethyl benzophenones, then through NaBH4Reduction and 1H-1, the condensation of 2,4- triazoles, obtain α-(1H-1,2,4- triazoles
Base) -4,4 '-dimethyl diphenylmethanes pass through acylation reaction with aceticanhydride afterwards, then through oximate, to obtain target product bent for hydrolysis
Azoles.The synthetic route is too long, and total recovery is low.
Route six
CN200710068474.X, US7538230, US7465749 etc. are starting using 4,4 '-dicyanobenzophenones
Raw material obtains 4,4 '-dicyano hexichol halomethanes through reduction, halogenating reaction, then with 1H-1, mesh is made in the condensation of 2,4- triazoles
Mark product Letrozole.
The route synthetic route is short, and reaction condition is not harsh, and total recovery is up to 54.8%.《Eur.J.Org.Chem.
2014,4115-4122》It is halogenated using mesyl chloride in second step, route total recovery will be changed and be promoted to 67%.But raw material 4,
The more difficult synthesis of 4 '-dicyanobenzophenones.
Route seven
CN201310676671.5 discloses a kind of method that one kettle way prepares Letrozole.Under aerobic conditions, to halobenzene first
Aldehyde, 4- halogenated methyl-benzaldehydes fully react under copper acetate and ammonia-catalyzed, and 1H-1 is added afterwards, and the reaction of 2,4- triazoles obtains
To target product Letrozole.The process route is novel, and step is succinct, but side reaction is more, yield 21-43%, and product is difficult to point
From being unsuitable for industrialized production.
It is not difficult to find out from said synthesis route, synthetic route has certain defect at present.In view of needing to meet industry
Change production requirement, i.e. synthetic route step is shorter, and reaction condition is not harsh, can select route one, four, six and seven.Again from production
The consideration of rate angle, six yield highest of route.So as can solving the synthesis of its 4,4 '-dicyanobenzophenone of existing raw material
Problem, the route will have good industrial applications foreground.
Invention content
It is an object of the invention to overcome deficiency in the prior art, a kind of system of the key intermediate of Letrozole is provided
Preparation Method, the preparation method route is novel, simple for process, and post-processing operation is convenient, and yield is high, is suitble to industrialized production.This hair
Bright purpose can be achieved through the following technical solutions：
A kind of preparation method of Letrozole key intermediate (I), it is characterised in that：By 2- (4- cyano-phenyls) formyl first
Sour (II) and 4- halogenated benzonitriles (III) reaction generate.
Wherein, the halogen of 4- halogenated benzonitriles (III) be chlorine, bromine, iodine or other similar to the substituent group of halogen, preferably chlorine or
Bromine.
The substituent group of similar halogen can be, but not limited to as-OMs ,-OTs ,-OCO-C1-6Alkyl ,-OTf ,-ONO2Deng.
In a preferred embodiment, intermediate (I) is by 2- (4- cyano-phenyls) formic acid (II) and 4- halogeno-benzenes
Nitrile (III) is under alkali, catalysts conditions, and in solvent prepared by one pot reaction.
In a preferred embodiment, raw material 2- (4- cyano-phenyls) formic acid (II) and 4- halogenated benzonitriles (III)
Molar ratio be 1: 0.5-5, preferably 1: 1.
In a preferred embodiment, the alkali for reacting used be selected from sodium bicarbonate, sodium carbonate, potassium carbonate, potassium phosphate,
Any one of sodium hydroxide, potassium hydroxide, cesium carbonate, sodium hydride, sodium methoxide, sodium ethoxide or potassium tert-butoxide.
In a preferred embodiment, the alkali for reacting used is 2- (4- cyano-phenyls) formic acid (II) dosage
1-50 times, preferably 2 times.
In a preferred embodiment, the solvent for reacting used is tetrahydrofuran, Isosorbide-5-Nitrae-dioxane, N, N- diformazans
Any one of base formamide, n,N-dimethylacetamide, dimethyl sulfoxide (DMSO), toluene, dimethylbenzene, N-Methyl pyrrolidone or
The mixed solution of arbitrary two kinds of solvents.
In a preferred embodiment, the solvent of reaction is the 1- of 2- (4- cyano-phenyls) formic acid (II) dosage
1000 times.
In a preferred embodiment, the catalyst of reaction is palladium catalyst, copper catalyst and ligand.
The palladium catalyst is selected from Pd (OAc)2、PdCl2、PdBr2、PdI2、Pd(PPh3)4、Pd(PPh3)2Cl2、 Pd2
(PPh3)2Cl4、Pd(acac)2Or Pd (dba)2。
The copper catalyst is selected from CuI, CuBr, CuOAc, CuCl, CuOTf, preferably CuI.
The ligand is 2,2 '-bipyridyls, 1,10- phenanthroline, pyridine, 4,7- diphenyl -1,10- phenanthroline, triphen
Base phosphorus, tricyclohexyl phosphine, tri-tert-butylphosphine, 1,1 '-bis- (diphenylphosphine) ferrocene, bis- diphenylphosphine -9, the 9- dimethyl of 4,5-
Xanthene, (±) -2,2 '-bis--(diphenyl phosphine) -1,1 '-dinaphthalene or arbitrary two kinds of ligands are used in mixed way, and preferably 1,10- phenanthrene is coughed up
Quinoline.
In a preferred embodiment, palladium catalyst is 2- (4- cyano-phenyls) formic acid (II) dosage
0.5%-20%.
In a preferred embodiment, copper catalyst is the 1%- of 2- (4- cyano-phenyls) formic acid (II) dosage
30%.
In a preferred embodiment, ligand is the 1%-40% of 2- (4- cyano-phenyls) formic acid (II) dosage.
In a preferred embodiment, the reaction temperature of reaction is 50-200 DEG C.
In a preferred embodiment, the time of reaction is 5-100 hours, preferably 24 hours.
It is raw material that the present invention, which selects 2- (4- cyano-phenyls) formic acid (II) and 4- halogenated benzonitriles (III), provides one
Kind route is novel, succinct efficient, it is only necessary to which that the preparation method of Letrozole key intermediate is made in single step reaction.The preparation method is kept away
The use for having exempted from corrosivity and toxic material, improves the safety of production, and equipment saving is environmental-friendly；And react behaviour
Make simple, favorable reproducibility, high income, good economy performance, and can ensure that the follow-up Letrozole that high-purity is prepared, is high-purity
The scale industrial production of Letrozole provide guarantee.
Description of the drawings
Fig. 1 is the HPLC chromatogram for the Letrozole being prepared by 1 gained intermediate (I) of embodiment, purity 99.9%.
Specific implementation mode
In order to better understand the content of the present invention, with reference to specific embodiment to technical scheme of the present invention do into
The explanation of one step, but specific embodiment is not meant to there are any restrictions to the present invention.
The raw materials used in the present invention and reagent can be prepared by a conventional method to obtain or commercially available.
Embodiment one
N,N-Dimethylformamide (200mL) is added in 500mL there-necked flasks, 2- (4- cyano benzene is sequentially added under nitrogen
Base) formic acid (II) (35.1g, 0.2mol), 4- bromos cyanophenyl (III) (36.3g, 0.2mol), cesium carbonate (40.0g,
0.4mol), PdCl2(1.79g, 0.01mol), CuI (3.8g, 0.02mol) and 2,2 '-bipyridyls (3.2g, 0.02mol) stir
It mixes, is warming up to 100 DEG C and reacts 12 hours, the reaction was complete that (2- (4- cyano-phenyls) formic acid content is less than for HPLC detections
1%) it, is cooled to room temperature, slowly plus water has solid precipitation.Solid extracts (50mL x 3) after being dissolved with ethyl acetate, and gained has
Machine is mutually washed with 5% aqueous hydrochloric acid solution (100mL) and saturated nacl aqueous solution (100mL) successively, anhydrous sodium sulfate drying,
Filtering, filtrate decompression are concentrated to give crude product, and crude product is recrystallized through methyl tertiary butyl ether(MTBE) (150mL), obtains white solid product
(42.2g, yield：90.9%).
Embodiment two
Isosorbide-5-Nitrae-dioxane (200mL) is added in 500mL there-necked flasks, 2- (4- cyano-phenyls) formyl is added under nitrogen
Formic acid (II) (35.1g, 0.2mol), 4- bromos cyanophenyl (III) (36.3g, 0.2mol), sodium ethoxide (27.3g, 0.4mol), Pd
(PPh3)4(11.8g, 0.01mol), CuBr (4.3g, 0.03mol), 1,10- phenanthroline (7.3g, 0.04mol) stir, heating
To 80 DEG C of back flow reactions 24 hours, the reaction was complete that (2- (4- cyano-phenyls) formic acid (III) content is less than for HPLC detections
1%) it, is cooled to room temperature, slowly plus elutriation goes out solid, and solid extracts (50mL x 3) after being dissolved with ethyl acetate.Gained is organic
It is mutually washed with 5% aqueous hydrochloric acid solution (100mL) and saturated nacl aqueous solution (100mL), anhydrous sodium sulfate drying, after filtering
Filtrate concentrates, and white solid product (41.9g, yield are recrystallized to give with methyl tertiary butyl ether(MTBE) (150mL)：90.3%).
Embodiment three
Dimethyl sulfoxide (DMSO) (200mL) is added in 500mL there-necked flasks, 2- (4- cyano-phenyls) formyl first is added under nitrogen
Sour (II) (35.1g, 0.2mol), 4- bromos cyanophenyl (III) (18.2g, 0.1mol), sodium hydroxide (40.1g, 1mol),
PdBr2(0.53g, 0.002mol), CuOAc (0.49g, 0.004mol), 1,10- phenanthroline (1.46g, 0.008mol) and three
Cyclohexyl phosphine (2.24g, 0.008mol), stirring, is warming up to 140 DEG C, reacts 5 hours, HPLC detections the reaction was complete (4- bromos
Cyanophenyl (III) content is less than 1%), it is cooled to room temperature, slowly plus elutriation goes out solid, and solid extracts after being dissolved with ethyl acetate
(50mL x 3).Gained organic phase is washed with 5% aqueous hydrochloric acid solution (100mL) and saturated nacl aqueous solution (100mL) successively
It washs, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, residue is recrystallized to give white with methyl tertiary butyl ether(MTBE) (150mL)
Color solid product (21.7g, yield：93.5%).
Example IV
N,N-dimethylacetamide (200mL) is added in 500mL there-necked flasks, 2- (4- cyano-phenyls) is added under nitrogen
Formic acid (II) (35.1g, 0.2mol), 4- bromos cyanophenyl (III) (72.6g, 0.4mol), potassium phosphate (85.7g,
0.4mol), Pd (OAc)2(0.45g, 0.002mol), CuOTf (12.8g, 0.06 mol), pyridine (9.7g, 0.12mol) and 4,
Bis- diphenylphosphine -9, the 9- xanthphos (2.32g, 0.004mol) of 5-, stirring are warming up to 120 DEG C, react 12 hours,
The reaction was complete for HPLC detections (2- (4- cyano-phenyls) formic acid (II) content is less than 1%), is cooled to room temperature, slowly adds water
Solid is precipitated, solid extracts (50mL x 3) after being dissolved with ethyl acetate.Gained organic phase with 5% aqueous hydrochloric acid solution
(100mL) and saturated nacl aqueous solution (100mL) wash, anhydrous sodium sulfate drying, filtering, and filtrate decompression is concentrated to give crude product, slightly
Product are recrystallized with methyl tertiary butyl ether(MTBE) (150mL), obtain white solid product (44.7g, yield：96.3%).
Embodiment five
Toluene (200mL) is added in 500mL there-necked flasks, 2- (4- cyano-phenyls) formic acid (II) is added under nitrogen
(35.1g, 0.2mol), 4- bromos cyanophenyl (III) (36.3g, 0.2mol), potassium tert-butoxide (45.1 g, 0.4mol), Pd
(acac)2(1.8g, 0.006mol), CuI (3.8g, 0.02mol), 4,7- diphenyl -1,10- phenanthroline (6.7g,
0.02mol), it stirs, is warming up to back flow reaction 48 hours, HPLC detections the reaction was complete (2- (4- cyano-phenyls) formic acid
(II) content is less than 1%), it is cooled to room temperature, slowly plus elutriation goes out solid, and solid extracts (50mL x after being dissolved with ethyl acetate
3).Gained organic phase is washed with 5% aqueous hydrochloric acid solution (100mL) and saturated nacl aqueous solution (100mL), anhydrous sodium sulfate
Dry, filtrate concentrates after filtering, residue with methyl tertiary butyl ether(MTBE) (150mL) be recrystallized to give white solid product (43.5g,
Yield：93.7%).
Embodiment six
With one gained midbody product (42.2g, 0.18mol) of embodiment for raw material, reference literature
《Eur.J.Org.Chem.2014,4115-4122》In preparation method, white solid Letrozole (36.4g, total recovery is made：
70.3%, HPLC：99.9%), HPLC chromatogram is as shown in Figure 1.
It should be pointed out that above-mentioned several preferred embodiments be technical solution of the present invention is made it is further unrestricted
It is described in detail, technical concept and feature only to illustrate the invention.Its object is to make person skilled in the art much of that
Solution present disclosure is simultaneously implemented according to this, and it is not intended to limit the scope of the present invention.It is all according to spirit of the invention
Made by equivalent change or modification, should be covered by the protection scope of the present invention.
Claims (10)
1. a kind of preparation method of Letrozole key intermediate (I), it is characterised in that：By 2- (4- cyano-phenyls) formic acid
(II) it is generated with 4- halogenated benzonitriles (III) reaction；
Wherein, the halogen of 4- halogenated benzonitriles (III) be chlorine, bromine, iodine or other similar to the substituent group of halogen, preferably chlorine or bromine.
2. preparation method according to claim 1, it is characterised in that：Intermediate (I) is by 2- (4- cyano-phenyls) formyl first
Sour (II) and 4- halogenated benzonitriles (III) are under alkali, catalysts conditions, and in solvent prepared by one pot reaction.
3. preparation method according to claim 1 or 2, it is characterised in that：2- (4- cyano-phenyls) formic acid (II) and
The raw material molar ratio of 4- halogenated benzonitriles (III) is 1:0.5-5, preferably 1:1.
4. preparation method according to claim 2, it is characterised in that：The alkali is selected from sodium bicarbonate, sodium carbonate, carbonic acid
Potassium, potassium phosphate, sodium hydroxide, potassium hydroxide, cesium carbonate, sodium hydride, sodium methoxide, sodium ethoxide or potassium tert-butoxide.
5. preparation method according to claim 4, it is characterised in that：The alkali is 2- (4- cyano-phenyls) formic acid
(II) 1-50 times of dosage, preferably 2 times.
6. preparation method according to claim 2, it is characterised in that：The reaction dissolvent is tetrahydrofuran, Isosorbide-5-Nitrae-dioxy
Six rings, N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide (DMSO), toluene, dimethylbenzene, N-Methyl pyrrolidone
Any one of or arbitrary two kinds of solvents mixed solution；Dosage is the 1- of 2- (4- cyano-phenyls) formic acid (II) dosage
1000 times.
7. preparation method according to claim 2, it is characterised in that：The catalyst of reaction is palladium catalyst, copper catalyst
And ligand.
8. preparation method according to claim 7, it is characterised in that：Palladium catalyst is Pd (OAc)2、PdCl2、PdBr2、
PdI2、Pd(PPh3)4、Pd(PPh3)2Cl2、Pd2(PPh3)2Cl4、Pd(acac)2Or Pd (dba)2；The copper catalyst is
CuI, CuBr, CuOAc, CuCl or CuOTf, preferably CuI；The ligand be 2,2'- bipyridyls, 1,10- phenanthroline, pyridine,
4,7- diphenyl -1,10- phenanthroline, triphenyl phosphorus, tricyclohexyl phosphine, tri-tert-butylphosphine, two cyclopentadienyls of 1,1'- bis- (diphenylphosphines)
Bis- diphenylphosphine -9,9- the xanthphos of iron, 4,5-, (±) -2,2'- pairs-(diphenyl phosphine) -1,1'- dinaphthalenes or arbitrary two
Kind ligand is used in mixed way, preferably 1,10- phenanthroline.
9. preparation method according to claim 7 or 8, it is characterised in that：Palladium catalyst is 2- (4- cyano-phenyls) formyl
The 0.5%-20% of formic acid (II) dosage；The copper catalyst is the 1%- of 2- (4- cyano-phenyls) formic acid (II) dosage
30%；The ligand is the 1%-40% of 2- (4- cyano-phenyls) formic acid (II) dosage.
10. preparation method according to claim 1 or 2, it is characterised in that：The reaction temperature of the reaction is 50-200
℃；Reaction time is 5-100 hours, preferably 24 hours.
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| CN112209851A (en) * | 2020-09-08 | 2021-01-12 | 山东斯瑞药业有限公司 | Extraction method of 4, 4-dicyanobenzophenone |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090221832A1 (en) * | 2008-02-28 | 2009-09-03 | Saltigo Gmbh | Process for preparing ketones from alpha-oxo carboxylates and aryl bromides |
| WO2015153381A2 (en) * | 2014-04-04 | 2015-10-08 | The Trustees Of Princeton University | Decarboxylative cross-coupling and applications thereof |
-
2018
- 2018-03-05 CN CN202110288382.2A patent/CN113072462A/en active Pending
- 2018-03-05 CN CN201810178582.0A patent/CN108409604A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20090221832A1 (en) * | 2008-02-28 | 2009-09-03 | Saltigo Gmbh | Process for preparing ketones from alpha-oxo carboxylates and aryl bromides |
| WO2015153381A2 (en) * | 2014-04-04 | 2015-10-08 | The Trustees Of Princeton University | Decarboxylative cross-coupling and applications thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112209851A (en) * | 2020-09-08 | 2021-01-12 | 山东斯瑞药业有限公司 | Extraction method of 4, 4-dicyanobenzophenone |
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