CN102491973A - Synthetic method for ZD (Zero Defects)-4054 - Google Patents
Synthetic method for ZD (Zero Defects)-4054 Download PDFInfo
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- CN102491973A CN102491973A CN2011104225299A CN201110422529A CN102491973A CN 102491973 A CN102491973 A CN 102491973A CN 2011104225299 A CN2011104225299 A CN 2011104225299A CN 201110422529 A CN201110422529 A CN 201110422529A CN 102491973 A CN102491973 A CN 102491973A
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- methylpyrazine
- tertiary butyl
- methoxyl group
- chloropyridine
- carbamate
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Abstract
The invention discloses a synthetic method for ZD-4054, belonging to the technical field of medicine synthesis. The technical scheme is as follows: using 3- methoxyl-5- methylpyrazine-2-amine as material; protecting amino by Boc acid anhydride, reacting with 2- chloropyridine-3-sulfonyl chloride to acquire intermediate tert-butyl-2- chloropyridine-3-sulfuryl(3- methoxyl-5- methylpyrazine-2-group) carbamic acid ester, then condensing with 4-(1,3,4- oxadiazole-2-group) phenyl boric acid to acquire tert-butyl group-2-(4-(1,3,4- oxadiazole-2-group)phenyl) pyridine-3- sulfonyl(3- methoxyl-5- methylpyrazine-2-group) carbamic acid ester; finally, de-protecting to acquire the ZD-4054. The synthetic method has high overall yield, simple operations and low synthetic cost.
Description
Technical field
The invention belongs to technical field of medicine synthesis, be specifically related to the compound method of anticarcinogen ZD-4054.
Technical background
ZD-4054, English name Zibotentan is a sulfidin analog derivative, its chemistry N-(3-methoxyl group-5-methyl-2-pyrazinyl) by name-2-[4-(1,3,4-oxadiazoles-2-yl) phenyl]-3-sulfidin.Its chemical structural formula is following:
ZD-4054 is the antitumour drug by Astrazeneca AB's exploitation, is a kind of oral specificity ET that effectively has
AReceptor antagonist, in vitro study shows that ZD-4054 and cell toxicity medicament taxol or Docetaxel coupling can suppress cell proliferation and short apoptosis more significantly than its respectively single usefulness in prostate cancer cell; ZD-4054 can suppress ET
AReceptor-mediated anti-apoptotic process, and do not influence ET
BReceptor-mediated short apoptotic signal path; In addition, ZD-4054 can suppress ET
21The cell invasion effect of mediation; In Proliferation of Human Ovarian Cell, ZD-4054 can suppress the epithelium-matter conversion that carcinogenic cells is converted into the aggressive phenotype; In breast cancer cell, ZD-4054 and arimedex or selective estrogen antagonist fulvestrant coupling can strengthen the restraining effect of on cell migration and invasion and attack.Therefore, ZD-4054 is a treatment prostate cancer, the potential drug of ovarian cancer and mammary cancer.
WO 964068EP and EP0832082 have disclosed ZD-4054 synthetic method, and its concrete route is following:
This method is a raw material with 3-methoxyl group-5-methylpyrazine-2-amine; Obtain midbody isobutyl--2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate with 2-chloropyridine-3-SULPHURYL CHLORIDE reaction again through isobutyl chlorocarbonate protection amino; Afterwards with the condensation of 4-(methoxycarbonyl) phenylo boric acid; Deprotection closes ring and obtains ZD-4054.
This method route is longer, has used hypertoxic hydrazine at penultimate stride, and final step pass ring productive rate is low, and synthetic cost is high, has increased the difficulty of last exquisite purifying.
Summary of the invention
The present invention can overcome the shortcoming of above synthetic route, and a kind of brand-new compound method is provided, and overall yield is high, and is easy and simple to handle, and synthetic cost is low.
Technical scheme of the present invention is: with 3-methoxyl group-5-methylpyrazine-2-amine is raw material; Amino through the protection of Boc acid anhydrides, obtain the midbody tertiary butyl-2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate with 2-chloropyridine-3-SULPHURYL CHLORIDE reaction again, afterwards with 4-(1; 3; 4-oxadiazole-2-yl) phenylo boric acid condensation, (4-(1,3 to obtain the tertiary butyl-2-; 4-oxadiazole-2-yl) pyridin-3-yl sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate phenyl), last deprotection obtains ZD-4054.
Concrete synthetic route is following:
Beneficial effect:
1, in order to reach above-mentioned requirements, be raw material with 4-(1,3,4-oxadiazole-2-yl) phenylo boric acid, the ring closure reaction that productive rate is low in advance, thereby improved utilization of materials, avoided several steps in the end to use the hydrazine reagent of severe toxicity.
2, with the Boc acid anhydrides as protective material, one-step removal protection has in the end reduced the difficulty of refining purifying.There is not bibliographical information before this route.
Embodiment
Through specific embodiment this invention is done further to describe below.
Embodiment 1
The first step: suc as formula the preparation of the midbody tertiary butyl 3-methoxyl group-5-methylpyrazine-2-aminocarbamic acid ester shown in the II
In the 2L there-necked flask, add suc as formula the methoxyl group of the 3-shown in the I-5-methylpyrazine-2-amine 50.0g; Dissolve with methylene dichloride 700mL; Add triethylamine 50.0mL again, the reaction solution mechanical stirring is cooled to 0-5 ℃ with ice-water bath; Slowly drip Boc acid anhydrides 78.4g, drip off afterreaction liquid and be heated to 30 ℃ of stirring reactions.The TLC detection reaction finishes the postcooling reaction solution.The refrigerative reaction solution is washed with the Hydrogen chloride of the 0.5mol/L of 300mL successively, and saturated sodium-chloride 500mL washes, and obtains oily liquids 80.1g, productive rate 93.2% after organic solvent is removed in decompression.
Second step: the preparation of the midbody tertiary butyl shown in formula III-2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate
In the 500mL there-necked flask, add tertiary butyl 3-methoxyl group-5-methylpyrazine-2-aminocarbamic acid ester 10.0g; With THF 200mL dissolving, the reaction solution magnetic agitation is cooled to 0-5 ℃ with ice-water bath; The careful sodium hydride solid 2.0g that adds; Add afterreaction liquid and under nitrogen protection, stirred 20 minutes, slowly add 2-chloropyridine-3-SULPHURYL CHLORIDE 10.6g, add afterreaction liquid and be raised to 50 ℃ of reactions of 2 hours post-heating of stirring at room.The TLC detection reaction finishes the postcooling reaction solution.The refrigerative reaction solution is poured into cancellation in the saturated sodium bicarbonate solution of 400mL, with ETHYLE ACETATE 200mL extraction product, the ETHYLE ACETATE concentrating under reduced pressure with obtaining obtains oily liquids 15.2g, directly carries out next step reaction, productive rate 88% without crossing column purification.
The 3rd step: suc as formula the preparation of the tertiary butyl-2-shown in the IV (4-(1,3,4-oxadiazole-2-yl) phenyl) pyridin-3-yl sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate
The 250mL there-necked flask under nitrogen protection, joins the tertiary butyl-2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate (4) 15.2g with four triphenyl phosphorus palladium 1.5g; 4-(1; 3,4-oxadiazole-2-yl) phenylo boric acid (5) 6.9g, glycol dimethyl ether 30mL; In the mixture of saturated sodium bicarbonate 5mL, with heating reflux reaction in the mixed solution oil bath.The TLC detection reaction finishes the postcooling reaction solution and adds ETHYLE ACETATE 200mL, filters, and the filtrating layering concentrates organic phase, and purifying through silicagel column obtains solid 14.0g, productive rate 73.0%.
The 4th step: the preparation of ZD-4054
In 50mL single port bottle, add the tertiary butyl-2-(4-(1,3,4-oxadiazole-2-yl) phenyl) pyridin-3-yl sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate 1.5g; Use the 15mL dissolve with methanol, add concentrated hydrochloric acid 1.0mL, the stirring at room reaction; The TLC detection reaction finishes; Regulate pH with sodium hydrogencarbonate and arrive the dense dry reaction liquid in neutral back, obtain ZD-40541.0g with the absolute ethyl alcohol recrystallization, productive rate 85%.
Embodiment 2
The first step: the preparation of midbody tertiary butyl 3-methoxyl group-5-methylpyrazine-2-aminocarbamic acid ester
In the 2L there-necked flask, add 3-methoxyl group-5-methylpyrazine-2-amine 10.0g,, add triethylamine 10.0mL again with methylene dichloride 140mL dissolving; The reaction solution mechanical stirring; Be cooled to 0-5 ℃ with ice-water bath, slowly drip Boc acid anhydrides 7.84g, drip off afterreaction liquid and be heated to 30 degree stirring reactions.The TLC detection reaction finishes the postcooling reaction solution.The refrigerative reaction solution is washed with the Hydrogen chloride of the 0.5mol/L of 30mL successively, and saturated sodium-chloride 100mL washes, and obtains oily liquids 17.0g, productive rate 98.8% after organic solvent is removed in decompression.
Second step: the preparation of the midbody tertiary butyl-2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate
In the 500mL there-necked flask, add tertiary butyl 3-methoxyl group-5-methylpyrazine-2-aminocarbamic acid ester 10.0g; With THF 200mL dissolving, the reaction solution magnetic agitation is cooled to 0-5 ℃ with ice-water bath; The careful sodium hydride solid 2.5g that adds; Add afterreaction liquid and under nitrogen protection, stirred 20 minutes, slowly add 2-chloropyridine-3-SULPHURYL CHLORIDE 10.6g, add afterreaction liquid and be raised to the stirring at room reaction.The TLC detection reaction finishes the postcooling reaction solution.The refrigerative reaction solution is poured into cancellation in the saturated sodium bicarbonate solution of 400mL, with ETHYLE ACETATE 200mL extraction product, the ETHYLE ACETATE concentrating under reduced pressure with obtaining obtains oily liquids 12.1g, directly carries out next step reaction, productive rate 70% without crossing column purification.
The 3rd step: the preparation of the tertiary butyl-2-(4-(1,3,4-oxadiazole-2-yl) phenyl) pyridin-3-yl sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate
The 250mL there-necked flask under nitrogen protection, joins the tertiary butyl-2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate 12.1g with four triphenyl phosphorus palladium 2.4g; 4-(1; 3,4-oxadiazole-2-yl) phenylo boric acid 5.5g, glycol dimethyl ether 30mL; In the mixture of saturated sodium bicarbonate 5mL, with 80 ℃ of reactions of heating in the mixed solution oil bath.The TLC detection reaction finishes the postcooling reaction solution and adds ETHYLE ACETATE 200mL, filters, and the filtrating layering concentrates organic phase, and purifying through silicagel column obtains solid 11.7g, productive rate 77%.
The 4th step: the preparation of ZD-4054
In 50mL single port bottle, add the tertiary butyl-2-(4-(1,3,4-oxadiazole-2-yl) phenyl) pyridin-3-yl sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate 1.5g; Use the 15mL dissolve with methanol, add concentrated hydrochloric acid 1.0mL, the stirring at room reaction; The TLC detection reaction finishes; Regulate pH with sodium hydrogencarbonate and arrive the dense dry reaction liquid in neutral back, obtain ZD-40541.0g with the absolute ethyl alcohol recrystallization, productive rate 85%.
Claims (4)
1. the compound method of a ZD-4054, its step is following:
(1) to be raw material, obtains suc as formula the tertiary butyl 3-methoxyl group shown in the II-5-methylpyrazine-2-aminocarbamic acid ester through tert-Butyl dicarbonate (Boc acid anhydrides) protection suc as formula the methoxyl group of the 3-shown in the I-5-methylpyrazine-2-amine;
(2) the tertiary butyl 3-methoxyl group-5-methylpyrazine-2-aminocarbamic acid ester and the tertiary butyl-2-chloropyridine-3-SULPHURYL CHLORIDE obtains the tertiary butyl-2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate shown in formula III through the alkaline purification reaction;
(3) tertiary butyl-2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate and 4-(1; 3; 4-oxadiazole-2-yl) the phenylo boric acid condensation obtains that (4-(1 suc as formula the tertiary butyl-2-shown in the IV; 3,4-oxadiazole-2-yl) phenyl) pyridin-3-yl sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate;
(4) tertiary butyl-2-(4-(1,3,4-oxadiazole-2-yl) phenyl) pyridin-3-yl sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate deprotection obtains suc as formula the ZD-4054 shown in the V.
2. compound method according to claim 1 is characterized in that: used alkali is sodium hydride in the step (2), and the mol ratio of 5 tertiary butyl 3-methoxyl groups-5-methylpyrazine-2-aminocarbamic acid ester and sodium hydride is 1: 1～2, and temperature of reaction is 0-60 ℃.
3. compound method according to claim 1; It is characterized in that catalyst system therefor is four triphenyl phosphorus palladiums in the step (3); The mass ratio of the tertiary butyl-2-chloropyridine-3-base sulphonyl (3-methoxyl group-5-methylpyrazine-2-yl) carbamate and catalyzer is 1: 0.05～0.3; Solvent for use is glycol dimethyl ether or dioxane, and temperature of reaction is 0-100 ℃.
4. compound method according to claim 1 is characterized in that acid used in the step 4 is hydrochloric acid.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996040681A1 (en) * | 1995-06-07 | 1996-12-19 | Zeneca Limited | N-heteroaryl-pyridinesulfonamide derivatives and their use as endothelin antagonists |
| WO1998040332A1 (en) * | 1997-03-07 | 1998-09-17 | Zeneca Limited | Process for the manufacture of arylsulfonyl chloride |
| CN1688365A (en) * | 2002-08-23 | 2005-10-26 | 阿斯利康(瑞典)有限公司 | Therapeutic use |
| WO2007010235A1 (en) * | 2005-07-19 | 2007-01-25 | Astrazeneca Ab | Ethanolamine salt of n- (3-methoxy-5-methylpyrazin-2yl) -2- (4- [1 , 3 , 4-0xadiaz0le-2-yl] phenyl) pyridine-3- sulphonamide |
| CN1922193A (en) * | 2004-02-20 | 2007-02-28 | 阿斯利康(瑞典)有限公司 | Chemical process |
-
2011
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996040681A1 (en) * | 1995-06-07 | 1996-12-19 | Zeneca Limited | N-heteroaryl-pyridinesulfonamide derivatives and their use as endothelin antagonists |
| WO1998040332A1 (en) * | 1997-03-07 | 1998-09-17 | Zeneca Limited | Process for the manufacture of arylsulfonyl chloride |
| CN1688365A (en) * | 2002-08-23 | 2005-10-26 | 阿斯利康(瑞典)有限公司 | Therapeutic use |
| CN1922193A (en) * | 2004-02-20 | 2007-02-28 | 阿斯利康(瑞典)有限公司 | Chemical process |
| WO2007010235A1 (en) * | 2005-07-19 | 2007-01-25 | Astrazeneca Ab | Ethanolamine salt of n- (3-methoxy-5-methylpyrazin-2yl) -2- (4- [1 , 3 , 4-0xadiaz0le-2-yl] phenyl) pyridine-3- sulphonamide |
Non-Patent Citations (3)
| Title |
|---|
| BIRGITTA STENSLAND，等: "N-(3-Methoxy-5-methylpyrazin-2-yl)-2-[4-(1,3,4-oxadiazol-2-yl)phenyl]pyridine-3-sulfonamide (ZD4054 Form 1)", 《ACTA CRYST.》, vol. 60, 25 September 2004 (2004-09-25), pages 1817 - 1819 * |
| JULIE A.BERGIN,等: "Synthesis of isotopically labelled ZD4054", 《JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS》, vol. 50, 31 December 2007 (2007-12-31), pages 432 - 2 * |
| 谢如刚，等: "《现代有机化学》", 31 January 2007, article "现代有机化学", pages: 94 - 2 * |
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Application publication date: 20120613 |