CN104530088A - Tert-butyl 2-amino-6,7-dihydro-5H-thiazolo[5,4-b]pyridyl-4-carboxylate and derivatives thereof, and their synthesis method - Google Patents
Tert-butyl 2-amino-6,7-dihydro-5H-thiazolo[5,4-b]pyridyl-4-carboxylate and derivatives thereof, and their synthesis method Download PDFInfo
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- CN104530088A CN104530088A CN201410742821.2A CN201410742821A CN104530088A CN 104530088 A CN104530088 A CN 104530088A CN 201410742821 A CN201410742821 A CN 201410742821A CN 104530088 A CN104530088 A CN 104530088A
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- 0 CC(C)(C)*C(N(CCC1)CC1=O)=O Chemical compound CC(C)(C)*C(N(CCC1)CC1=O)=O 0.000 description 2
- LZNIMGWYMCZLLL-UHFFFAOYSA-N CC(C)(C)OC(N(CCC1)c2c1nc(N)[s]2)=O Chemical compound CC(C)(C)OC(N(CCC1)c2c1nc(N)[s]2)=O LZNIMGWYMCZLLL-UHFFFAOYSA-N 0.000 description 2
- CSPCDBSWKMEASZ-UHFFFAOYSA-N CC(C)(C)OC(N(CCCC1=O)C1Br)=O Chemical compound CC(C)(C)OC(N(CCCC1=O)C1Br)=O CSPCDBSWKMEASZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
The invention discloses a novel drug compound intermediate tert-butyl 2-amino-6,7-dihydro-5H-thiazolo[5,4-b]pyridyl-4-carboxylate and derivatives thereof, and the derivatives comprise 4,5,6,7-tetrahydro-thiazolo[5,4-b]pyridyl-2-amine, tert-butyl 2-chloro-6,7-dihydro-4H-thiazolo[5,4-b]pyridyl-4-carboxylate and tert-butyl 2-bromo-6,7-dihydro-4H-thiazolo[5,4-b]pyridyl-4-carboxylate. Through further synthesis modification, a series of drug compounds with latent biological activity can be derived.
Description
Technical field
The invention belongs to technical field of organic synthesis, relate to amino-6, the 7-dihydro-5H-thiazoles of a kind of new pharmaceutical intermediate 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester and derivative thereof, and their synthetic method.
Background technology
2-amino-6,7-dihydro-4H-thiazole also [5,4-c] pyridine-5-carboxylic acid tert-butyl ester (A) and 2-amino-6,7-dihydro-4H-thiazole also [4,5-c] pyridine-5-carboxylic acid tert-butyl ester (B) is important pharmaceutical intermediate (structural formula is shown in formula 1 and formula 2 respectively).This compounds, after further synthetic modification, can be converted into and have bioactive medicine compounds.Compound (A) is the compounds precursors that a class has pharmacologically active, its bioactive molecule can suppress hedgehog pathway signal (Hedgedog Pathway Signaling), thus potentially for Tumor suppression growth, treatment comprises the disease of carcinoma of the pancreas and prostate cancer.What formula 3 was announced for World Intellectual Property Organization applies for a patent one of this compounds disclosed in WO2014/113191.
About synthesis existing a lot of report so far of amino-6, the 7-dihydro-4H-thiazoles of 2-also [5,4-c] pyridine-5-carboxylic acid tert-butyl ester (A).Wherein more representational synthetic route as shown in Equation 4.
Japanese publication patent JP2010/120852A discloses 2-amino-6, the 7-dihydro-4H-thiazole also synthesis of [4,5-c] pyridine-5-carboxylic acid tert-butyl ester (B) and related application, and its synthetic route as shown in Equation 5.
Summary of the invention
The present invention is intended to synthesize a kind of new medical compounds intermediate 2-amino-6,7-dihydro-5H-thiazole also [5,4-b] the Pyridine-4-carboxylic acid tert-butyl ester (C) and derivative thereof, this compound is structurally similar with (B) with compound (A); And as precursor structure, after further synthetic modification is carried out to this compound and derivative thereof, can derive and a series of there is bioactive molecule.
For achieving the above object, the technical solution adopted in the present invention is as follows:
A kind of pharmaceutical intermediate 2-amino-6,7-dihydro-5H-thiazole also [5,4-b] the Pyridine-4-carboxylic acid tert-butyl ester (C) (structural formula 6), and its derivative comprises 4,5,6,7-tetrahydrochysene-thiazole also [5,4-b] pyridine-2-amine (D) (structural formula 7), chloro-6, the 7-dihydro-4H-thiazoles of 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (E) (structural formula 8) and 2-bromo-6,7-dihydro-4H-thiazole is [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (F) (structural formula 9) also.
The present invention also provides the synthetic method of described intermediate, adopts following technical scheme:
Adopt one of following two kinds of methods amino-6,7-dihydro-5H-thiazoles of synthesis 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C):
(1) first with 1-tertbutyloxycarbonyl-3-piperidone (SM) for raw material, adopt amino-6, the 7-dihydro-5H-thiazoles of one of following two kinds of methods synthesis 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C).
Method I
SM and bromizating agent N-bromo-succinimide (NBS) generate the bromo-3-oxo-piperidine of intermediate 2--1-carboxylic acid tert-butyl ester (1) under radical initiator Diisopropyl azodicarboxylate (AIBN) acts on, described intermediate and thiocarbamide Cheng Huan, obtain compound (C), this route as shown in Equation 10.
Method II
SM and tetramethyleneimine form intermediate 5-pyrrolidin-1-yl-3 under 4-toluene sulfonic acide (PSA) catalysis, 4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2), described intermediate and sulphur and cyanamide are obtained by reacting compound (C), and this route as shown in Equation 11.
The method that aforesaid method II and Japanese Patent JP2010/120852A reports is similar, but only report 2-amino-6,7-dihydro-4H-thiazole also [4,5-c] pyridine-5-carboxylic acid tert-butyl ester in Japanese Patent, i.e. compound (B), and unexposed the compounds of this invention (C).The present invention found through experiments can be separated while obtaining compound (B) and obtains compound (C), but the productive rate of the target product that method II obtains (C) wants ratio method I lower; The productive rate of gained compound (B) and patent report are quite (15%).
(2) amino-6, the 7-dihydro-5H-thiazoles of 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C) by de--CO
2bu-t (Boc) protecting group synthetic compound (D).
Compound (C) sloughs Boc under trifluoroacetic acid (TFA) effect, and then add hydrogenchloride dioxane solution and obtain compound (D), this route as shown in Equation 12.
(3) amino-6, the 7-dihydro-5H-thiazoles of 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C) by diazotization reaction synthetic compound (E) and compound (F).
Compound (C) is under Isopentyl nitrite effect, and be obtained by reacting compound (E) and compound (F) with cupric chloride and cupric bromide respectively, this route as shown in Equation 13.
The present invention has synthesized new medical compounds intermediate 2-amino-6,7-dihydro-5H-thiazole also [5,4-b] the Pyridine-4-carboxylic acid tert-butyl ester (C), and derivative 4,5,6,7-tetrahydrochysene-thiazole is [5,4-b] pyridine-2-amine (D), chloro-6, the 7-dihydro-4H-thiazoles of 2-also [5 also, 4-b] the Pyridine-4-carboxylic acid tert-butyl ester (E) and 2-bromo-6,7-dihydro-4H-thiazole also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (F), this compounds (C, D, E and F) and synthesis be showed no any bibliographical information so far.As precursor structure, after further synthetic modification is carried out to this compound and derivative thereof, can derive and a series of there is bioactive molecule.
Describe the present invention below in conjunction with specific embodiment.Protection scope of the present invention is not limited with embodiment, but is limited by claim.
Embodiment
Below by specific embodiment, technical solutions according to the invention are further described in detail, but are necessary to point out that following examples are only for the description to summary of the invention, do not form limiting the scope of the invention.
The synthesis (method I) of amino-6, the 7-dihydro-5H-thiazoles of embodiment 12-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C)
Step 1) the bromo-3-oxo-piperidine of 2--1-carboxylic acid tert-butyl ester (1)
1-tertbutyloxycarbonyl-3-piperidone (SM) (36g, 180mmol) be dissolved in 500ml tetracol phenixin, then NBS (32g is added successively, 180mmol) form orange suspension with AIBN (90mg), system is heated to backflow, and the system after 3 hours that stirs is cooled to 0 DEG C, filters, wash with methylene dichloride, be directly used in after gained filtrate is concentrated and prepare compound (C).
Step 2) amino-6, the 7-dihydro-5H-thiazoles of 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C)
(1) that previous step obtained is dissolved in 300ml DMF, adds thiocarbamide (13.8g, 180mmol) wherein, then stir 1 hour at 75 DEG C, in system, add saturated sodium bicarbonate solution after being cooled to room temperature, be then extracted with ethyl acetate, dry, separating-purifying is carried out with column chromatography after concentrated, obtain 2-amino-6,7-dihydro-5H-thiazole also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C) 22g, in light yellow solid, productive rate 48%.
MS(EI)m/z(M+H)
+256.2；
1H NMR(CDCl
3，400MHz)δ(ppm)4.76(br，2H)，3.71(t，2H)，2.62(t，2H)，1.98(m，2H)，1.53(s，9H)。
The synthesis (method II) of amino-6, the 7-dihydro-5H-thiazoles of embodiment 22-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C)
Step 1) 5-pyrrolidin-1-yl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2)
1-tertbutyloxycarbonyl-3-piperidone (SM) (48g, 241mmol), Pyrrolidine (21ml, 241mmol) He one hydration tosic acid (0.23g, 1mmol) be dissolved in 130ml hexanaphthene, system is heated to backflow, and the water that reaction generates is removed by water-and-oil separator.System after 3 hours of reacting is cooled to room temperature, is directly used in and prepares compound (C) after concentrated.
Step 2) amino-6, the 7-dihydro-5H-thiazoles of 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C)
(1) that previous step obtained is dissolved in 150ml methyl alcohol, sublimed sulphur (7.7g is added wherein under ice-water bath condition, 241mmol), then cyanamide (10.7g is dripped, methanol solution 80ml 255mmol), drip off rear continuation and react half an hour at 0 DEG C, naturally cool to rt while stirring overnight.After methyl alcohol is revolved, saturated sodium bicarbonate solution is added in system, then be extracted with ethyl acetate, dry, carry out separating-purifying with column chromatography after concentrated and obtain 2-amino-6,7-dihydro-5H-thiazole also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C) 16.7g, in light yellow solid, productive rate 27%.LC-MS and
1h-NMR analyzes collection of illustrative plates and step 2 in method I) product that obtains is identical.Be separated simultaneously and obtain 2-amino-6,7-dihydro-4H-thiazole also [4,5-c] pyridine-5-carboxylic acid tert-butyl ester (B) 9.2g, in light yellow solid, productive rate 15%.
MS(EI)m/z(M+H)
+256.2；
1H NMR(CDCl
3，400MHz)δ(ppm)5.12(br，2H)，4.37(s，2H)，3.70(t，2H)，2.65(t，2H)，1.48(s，9H)。
The synthesis of embodiment 34,5,6,7-tetrahydrochysenes-thiazole also [5,4-b] pyridine-2-amine (D)
By 2-amino-6,7-dihydro-5H-thiazole also [5,4-b] the Pyridine-4-carboxylic acid tert-butyl ester (C) (5.1g, 20mmol) is dissolved in 40ml methylene dichloride, drips 30ml trifluoroacetic acid at 0 DEG C, 1 hour is at room temperature stirred after dripping off, then in system, add the dioxane solution (6ml, 24mmol) of 4M hydrogenchloride, have solid to separate out, filter, wash with methylene dichloride, obtain product 4,5,6,7-tetrahydrochysene-thiazole is [5,4-b] pyridine-2-amine (D, hydrochloride) 3.2g also, in light yellow solid, productive rate 85%.
MS(EI)m/z(M+H)
+156.0；
1H NMR(D
2O，400MHz)δ(ppm)3.42(t，2H)，2.58(t，2H)，2.06(m，2H)。
The synthesis of chloro-6, the 7-dihydro-4H-thiazoles of embodiment 42-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (E)
Under room temperature condition, to in 125ml acetonitrile, add cupric chloride dihydrate (8.2g successively, 48mmol) with Isopentyl nitrite (7g, 60mmol), system is heated to 55 DEG C, 2-amino-6 is added wherein after 5 minutes, 7-dihydro-5H-thiazole also [5, 4-b] the Pyridine-4-carboxylic acid tert-butyl ester (C) (10.2g, 40mmol), react after keeping this temperature stir about half an hour, system cools, after revolving desolventizing, add saturated sodium bicarbonate and each 80ml of ethyl acetate, cross and filter insolubles, isolate organic phase, aqueous phase is extracted with ethyl acetate 2 times, the organic phase saturated common salt merged is washed, dry, carry out separating-purifying with column chromatography after concentrated and obtain 2-chloro-6, 7-dihydro-4H-thiazole also [5, 4-b] the Pyridine-4-carboxylic acid tert-butyl ester (E) 2.2g, in off-white color solid, productive rate 20%.
MS(EI)m/z(M+H)
+275.0/277.0；
1H NMR(CDCl
3，400MHz)3.77(t，2H)，2.80(t，2H)，2.06(m，2H)，1.50(s，9H)。
The synthesis of bromo-6, the 7-dihydro-4H-thiazoles of embodiment 52-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (F)
Under room temperature condition, to in 125ml acetonitrile, add cupric bromide (10.8g successively, 48mmol) with Isopentyl nitrite (7g, 60mmol), system is heated to 55 DEG C, 2-amino-6 is added wherein after 5 minutes, 7-dihydro-5H-thiazole also [5, 4-b] the Pyridine-4-carboxylic acid tert-butyl ester (C) (10.2g, 40mmol), react after keeping this temperature stir about half an hour, system cools, after revolving desolventizing, add saturated sodium bicarbonate and each 80ml of ethyl acetate, cross and filter insolubles, isolate organic phase, aqueous phase is extracted with ethyl acetate 2 times, the organic phase saturated common salt merged is washed, dry, carry out separating-purifying with column chromatography after concentrated and obtain 2-bromo-6, 7-dihydro-4H-thiazole also [5, 4-b] the Pyridine-4-carboxylic acid tert-butyl ester (F) 2.8g, in light yellow solid, productive rate 22%.
MS(EI)m/z(M+H)
+318.9/320.9；
1H NMR(CDCl
3，400MHz)δ(ppm)3.73(t，2H)，2.81(t，2H)，1.99(m，2H)，1.48(s，9H)。
Claims (2)
1. the pharmaceutical intermediate 2-amino-6 of structure shown in following formula, 7-dihydro-5H-thiazole also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C), and derivative 4,5,6,7-tetrahydrochysene-thiazole is [5,4-b] pyridine-2-amine (D), 2-chloro-6 also, 7-dihydro-4H-thiazole also [5,4-b] the Pyridine-4-carboxylic acid tert-butyl ester (E) and bromo-6, the 7-dihydro-4H-thiazoles of 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (F).
。
2. the preparation method of amino-6, the 7-dihydro-5H-thiazoles of 2-according to claim 1 also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester and derivative thereof, comprises the following steps:
1) first with 1-tertbutyloxycarbonyl-3-piperidone (SM) for raw material, adopt amino-6, the 7-dihydro-5H-thiazoles of one of following two kinds of methods synthesis 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C)
Method I
SM and bromizating agent N-bromo-succinimide generate the bromo-3-oxo-piperidine of intermediate 2--1-carboxylic acid tert-butyl ester (1) under the effect of radical initiator Diisopropyl azodicarboxylate, and described intermediate and thiocarbamide Cheng Huan obtain compound (C);
Method II
SM and tetramethyleneimine form intermediate 5-pyrrolidin-1-yl-3,4-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (2) under the catalysis of 4-toluene sulfonic acide, and described intermediate and sulphur and cyanamide are obtained by reacting compound (C);
2) amino-6, the 7-dihydro-5H-thiazoles of 2-also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (C) by Deprotection-CO
2bu-t synthetic compound 4,5,6,7-tetrahydrochysenes-thiazole is [5,4-b] pyridine-2-amine (D) also
Compound (C) sloughs-CO under trifluoroacetic acid effect
2bu-t, then adds the hydrochloride that hydrogenchloride dioxane solution obtains compound (D);
3) 2-amino-6,7-dihydro-5H-thiazole also [5,4-b] the Pyridine-4-carboxylic acid tert-butyl ester (C) is by diazotization reaction synthetic compound 2-chloro-6,7-dihydro-4H-thiazole also [5,4-b] the Pyridine-4-carboxylic acid tert-butyl ester (E) and compound 2-bromo-6,7-dihydro-4H-thiazole also [5,4-b] Pyridine-4-carboxylic acid tert-butyl ester (F)
Compound (C), under Isopentyl nitrite effect, is obtained by reacting compound (E) and compound (F) respectively with cupric chloride or cupric bromide.
。
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| CN107739350A (en) * | 2017-09-26 | 2018-02-27 | 天津大学 | A kind of method for synthesizing 2 aminothiazole derivs |
| CN109134510A (en) * | 2018-11-13 | 2019-01-04 | 井冈山大学 | Prepare 2- amino -5-CBZ-4, the new method of 5,6,7- tetrahydro-thiazoles simultaneously [5,4-C] pyridine |
| CN114507245A (en) * | 2022-02-23 | 2022-05-17 | 江苏丽源医药有限公司 | Preparation method of idoxaban and intermediate thereof |
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| CN109134510A (en) * | 2018-11-13 | 2019-01-04 | 井冈山大学 | Prepare 2- amino -5-CBZ-4, the new method of 5,6,7- tetrahydro-thiazoles simultaneously [5,4-C] pyridine |
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