KR20140118463A - Method for preparing thienopyrimidine compounds - Google Patents
Method for preparing thienopyrimidine compounds Download PDFInfo
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- KR20140118463A KR20140118463A KR1020130034436A KR20130034436A KR20140118463A KR 20140118463 A KR20140118463 A KR 20140118463A KR 1020130034436 A KR1020130034436 A KR 1020130034436A KR 20130034436 A KR20130034436 A KR 20130034436A KR 20140118463 A KR20140118463 A KR 20140118463A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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Abstract
Description
The present invention relates to a method for producing a thienopyrimidine compound, an intermediate used therefor and a method for producing the same.
Recently, studies have been actively conducted to control the activity of protein kinase to prevent or treat diseases related thereto. In particular, attempts have been made to control the activity of protein kinases such as FGFR, Bcr-Abl, and Raf using derivatives having a thieno [3,2-d] pyrimidine structure.
For example, PCT Publication Nos. WO 2011/093672 A2 and WO 2011/093684 A2 disclose various thieno [3,2-d] pyrimidine derivatives with inhibitory activity on protein kinases. According to these prior arts, a thieno [3,2-d] pyrimidine-7-carboxylic acid compound (formula a1 or a1 ') is prepared as an intermediate, and various thienopyrimidine derivatives Are synthesized.
However, in order to prepare the above intermediate (formula (a1) or (a1 ')), several steps of synthesis are necessary as shown in the following reaction formula (1). In addition, since an intermediate (a4) containing a protecting group (AcO < - >) is used in the molecule, a deprotection reaction such as hydrolysis is required and thus contains an ineffective element in the synthesis step. In addition, the compound of formula (a1) is likely to be unstable under acidic or basic conditions, and is highly likely to decompose upon long-term storage. In order to solve this problem, a compound of formula (a1 ') in which another protecting group (MeS-) is introduced is prepared and used. However, in order to synthesize an active derivative, another deprotection reaction is required, Are increased.
[Reaction Scheme 1]
PCT Publication No. WO 2011/025940 Al also discloses thieno [3,2-d] pyrimidine derivatives having inhibitory activity to protein kinases and the like. According to the prior art, methyl 4-chlorothieno [3,2-d] pyrimidine-7-carboxylate (Formula a3) is prepared as shown in Reaction Scheme 2 below, and then hydrolysis Thieno [3,2-d] pyrimidine-7-carboxylic acid (formula a1) is prepared. Then, the compound of formula (a1) is transformed into the compound of formula (a2) through chlorination to be used for the synthesis of the derivative.
However, in order to prepare the above intermediates, as shown in Scheme 2, volatile bromine The use of liquid at high temperature lowers the ease of operation, and is harmful to health and has a problem of stability, and it is not suitable for mass production because it requires expensive Pd catalyst and high pressure carbon dioxide gas. In order to obtain the compound of formula (a1), the compound of formula (a3) must undergo a hydrolysis reaction, and the compound of formula (a3) is likely to be unstable under basic hydrolysis conditions. In addition, the compound of formula (a1) is the same compound as in Reaction Scheme 1, which implies the possibility of instability in long-term storage.
[Reaction Scheme 2]
[Reaction Scheme 3]
As shown in the above prior art, in the conventional synthesis route for preparing various thienopyrimidine derivatives, a process for synthesizing an intermediate compound (for example, a chemical formula a1, chemical formula a1 ', chemical formula a3, etc.) And difficult or costly catalysts or harmful components are used, so that mass production of thienopyrimidine compounds is difficult, and there is a problem that it is harmful to the environment.
From this point of view, there is a need to simplify the synthesis process of complicated and difficult intermediates to develop a process that is more suitable for mass production of thienopyrimidine compounds and is environmentally harmless and safe.
An object of the present invention is to provide a novel method for preparing a thienopyrimidine compound suitable for mass production and harmless to the environment, an intermediate used therefor and a method for producing the same.
According to the above object, the present invention provides a process for preparing a compound of formula (I), which comprises: (a) halogenating a compound of formula (IV) (b) oxidizing the compound of formula (3) to obtain a compound of formula (2); And (c) subjecting the compound of formula (2) to an oxidation reaction to give 4-hydroxytneno [3,2-d] pyrimidine-7-carboxylic acid of formula
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
Wherein X is halogen; Z is halogen or hydroxy.
According to another aspect of the present invention, there is provided a 4-hydroxyne [3,2-d] pyrimidine-7-carboxylic acid of the above formula (1).
According to another aspect of the present invention, there is provided a process for preparing a compound of formula (I), comprising the steps of: (a) And (d) chlorinating the compound of formula (1).
[Chemical Formula 5]
The method for preparing the thienopyrimidine compound according to the present invention uses a lower-priced reagent than that of the prior art and is suitable for mass production because it is centered on the reaction at room temperature and has no purification step. Particularly in the preparation of the intermediate compound, It is efficient in terms of time and cost since it is possible to produce high purity intermediates using only harmless and environmentally friendly reagents.
Hereinafter, the present invention will be described more specifically.
Preparation of 4-Hydroxyt eno [3,2-d] pyrimidine-7-carboxylic acid (compound of formula 1)
The present invention provides a process for the preparation of 4-hydroxyt eno [3,2-d] pyrimidine-7-carboxylic acid which is used as an intermediate in the preparation of various thienopyrimidine compounds.
The intermediate of the present invention is prepared according to the synthesis route of the following reaction formula (4).
[Reaction Scheme 4]
Wherein X is halogen; Z is halogen or hydroxy.
The synthesis procedures and conditions are described in detail in each step below.
Synthesis step (a)
Step (a) is a reaction step of synthesizing the compound of formula (3) by halogenating the compound of formula (4).
As the halogenating agent for the halogenation reaction, brominating agents such as N-bromosuccinimide, bromine (liquid) and pyridinium tribromide; Chlorinating agents such as chlorine (gas), SO 2 Cl 2 , N-chlorosuccinimide; Iodinating agents such as iodine and N-iodosuccinimide; Or a mixture thereof.
The reaction temperature of the halogenation reaction is not limited thereto, but may be in the range of 80 ° C to 85 ° C.
As the reaction solvent for the halogenation reaction, benzene, carbon tetrachloride, chloroform, methylene chloride, acetonitrile Or a mixed solvent thereof may be used.
After the halogenation reaction, the compound of Formula 3 may be prepared by washing with a non-polar solvent such as benzene, hexane, ether, acetonitrile, or a polar solvent.
The compound of Formula 4, which is used as a starting material in this step, can be prepared as shown in Reaction Scheme 5 below.
[Reaction Scheme 5]
Wherein Z is halogen.
The specific reaction conditions of the above Reaction Scheme 5 can be found in PCT Publication No. WO 2011/093672 or WO 2011/093684.
Synthesis step (b)
Step (b) is a step of oxidizing the compound of formula (3) to obtain the compound of formula (2).
The oxidizing agent for the oxidation reaction may be an amine oxide-based oxidizing agent. Preferably, as the amine oxide-based oxidizing agent, N-methylmorpholine N-oxide, pyridine N-oxide, trialkyl N-oxide or a mixture thereof may be used.
The oxidation reaction may be carried out in a polar aprotic solvent, for example, in acetonitrile, acetone, tetrahydrofuran or a mixed solvent thereof.
The reaction temperature of the oxidation reaction may be in a range of 0 ° C to 50 ° C, and more preferably in a range of room temperature to 40 ° C.
The reaction time of the oxidation reaction may be 0.5 to 48 hours.
If necessary, the crude product obtained in this step can be purified by using a solvent such as cyclohexane, cyclohexane / 2-propanol, diethylether, diethylether / methanol and the like.
Synthesis step (c)
Step (c) is a step of oxidizing the compound of formula (2).
As the oxidizing agent, NaClO 2 , NaOCl, hydrogen peroxide or a mixture thereof can be used.
The oxidation reaction may be carried out under the sulfamic acid (sulfamic acid), DMSO, KH 2 PO 4, NaH 2 PO 4 , or the presence of a mixture thereof.
The reaction temperature of the oxidation reaction may be, but is not limited to, To 50 < 0 > C.
If necessary, the obtained product can be purified by trituration or recrystallization in a solvent.
4-Hydroxyt eno [3,2-d] pyrimidine-7-carboxylic acid (compound of formula (I)
The present invention also provides 4-hydroxy eno [3,2-d] pyrimidine-7-carboxylic acid of Formula 1 above.
Method for producing thienopyrimidine compound using compound of formula (1) as an intermediate
The compound of Chemical Formula 1 may be useful for the preparation of a thienopyrimidine compound of Chemical Formula 5 as disclosed in PCT Patent Publication No. WO 2011/025940 Al (ARRAY BIOPHARMA INC.).
Specifically, the compound of the following formula (5) can be prepared by chlorinating the compound of the formula (1) of the present invention.
[Chemical Formula 5]
More specifically, the compound of formula (5) may be prepared by the steps of (a) to (c) above to obtain the compound of formula (1); And (d) chlorinating the compound of formula (1).
Chlorination agents for the chlorination reaction include, but are not limited to, SOCl 2 , POCl 3 , oxalyl chloride, PCl 3 , PCl 5 Or a mixture thereof.
Hereinafter, the present invention will be described as a more specific example. However, the scope of the present invention is not limited to these specific examples.
Example 1: Preparation of 4-hydroxyne [3,2-d] pyrimidine-7-carboxylic acid (Formula 1)
Step 1) 7-Methylthieno [3,2-d] pyrimidin-4 (3H)
According to the method described in PCT Laid-Open Patent Publication No. WO 2011/093672 or WO 2011/093684, the title compound was prepared.
Step 2) 4-Chloro-7-methylthieno [3,2-d] pyrimidine
Methylthieno [3,2-d] pyrimidin-4 (3H) -one prepared in the above step 1 was used to prepare a compound represented by the formula (I) described in PCT Patent Publication No. WO 2011/093672 or WO 2011/093684 According to the method, the title compound was prepared.
Step 3) 7- (Bromomethyl) -4-chlorothieno [3,2-d] pyrimidine
To a solution of 4-chloro-7-methylthieno [3,2-d] pyrimidine (10 g, 54.2 mmol) prepared in the above step 2 in benzene (100 mL) and stirring was added N-bromosuccinimide NBS, 10 g, 56.1 mmol) was added and benzoyl peroxide (1.0 g, 4.1 mmol) was added. The reaction mixture was stirred at 80 < 0 > C for 5 hours, cooled and then hexane (50 mL) was added. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as the crude product. The crude product obtained was used in the next step without purification.
1 H-NMR (300MHz, CDCl 3): δ9.09 (s, 1H), 8.10 (s, 1H), 4.79 (s, 2H).
Step 4) 4-Chlorothieno [3,2-d] pyrimidine-7-carbaldehyde
(15 g, 54.2 mmol) was added to acetonitrile (100 mL), and the solution was added to a stirred solution of the crude product, 7- (bromomethyl) -4-chlorothieno [3,2- d] pyrimidine , N-methylmorpholine N-oxide (14.7 g, 108.4 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 15 hours, and the resulting solid was filtered and washed with acetonitrile. Water (50 mL) was added to the filtrate and concentrated under vacuum to remove the acetonitrile. The aqueous layer was extracted three times with dichloromethane, and the obtained organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound as a crude product. The crude product obtained was used in the next step without purification.
1 H-NMR (300MHz, DMSO -d6): δ10.30 (s, 1H), 9.39 (s, 1H), 9.20 (s, 1H).
Step 5) Preparation of 4-Hydroxyne [3,2-d] pyrimidine-7-carboxylic acid
4-chlorothieno [3,2-d] pyrimidine-7-carbaldehyde (10 g, 50 mmol) prepared in step 4 was dissolved in t-BuOH / THF / H 2 O (1: , Sulfamic acid (16.3 g, 166 mmol) was added to a solution prepared by dissolving KH 2 PO 4 (49.6 g, 364 mmol) and NaClO 2 (15.0 g, 166 mmol) in water 200 mL) at 0 < 0 > C. After 2 hours, the volatiles were removed by distillation and the resulting solid was filtered and washed with water to give the title compound as a primary. The filtered aqueous solution was extracted with methylene chloride (total of 300 mL, 3 times), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude title product as a crude product. To the vessel was added the title compound of the first step and the title compound obtained in the second step, and ethyl acetate (50 mL) was added thereto, followed by stirring at room temperature for 2 hours. The resulting solid was filtered, washed with ethyl acetate (10 mL) and dried at 50 < 0 > C for 15 hours to give the title compound (3.15 g, 16 mmol; yield 30%, total 3 steps, steps 3-5).
1 H-NMR (300MHz, DMSO -d6): δ8.81 (s, 1H), 8.26 (s, 1H).
Example 2: Preparation of 4-chlorothieno [3,2-d] pyrimidine-7-carbonyl chloride (Formula 5)
4-Hydroxythieno [3,2-d] pyrimidine-7-carboxylic acid (5 g, 25.5 mmol) obtained in Example 1 above was added to thionyl chloride (50 mL). DMF (0.1 mL) was added to the reaction mixture, followed by stirring at 80 ° C for 2 hours. After cooling to room temperature, the thionyl chloride was removed in vacuo and the residue was co-evaporated with chloroform. The resulting solid was mixed with hexane and filtered to give the title compound (5.35 g, 23.0 mmol, 90% yield).
1 H-NMR (300MHz, DMSO -d6): δ9.20 (s, 1H), 9.14 (s, 1H).
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is clearly understood that the same is by way of illustration and example only and is not to be taken by way of limitation, It is to be understood that the invention may be practiced within the scope of the appended claims.
Claims (15)
(b) oxidizing the compound of formula (3) to obtain a compound of formula (2); And
(c) a step of oxidizing the compound of formula (2) to produce 4-hydroxyanth [3,2-d] pyrimidine-7-carboxylic acid:
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
Wherein X is halogen; Z is halogen or hydroxy.
In step (a), the halogenation reaction is carried out in the presence of a base such as N-bromosuccinimide, bromine (liquid), pyridinium tribromide, chlorine (gas), SO 2 Cl 2 , N-chlorosuccinimide, iodine , N-iodosuccinimide, N-iodosuccinimide and mixtures thereof.
Wherein in step (a), the reaction temperature of the halogenation reaction is in the range of 80 캜 to 85 캜.
In the step (a), a solvent selected from the group consisting of benzene, carbon tetrachloride, chloroform, methylene chloride, acetonitrile and a mixed solvent thereof is used for the halogenation reaction.
Wherein in step (b), an amine oxide-based oxidizing agent is used for the oxidation reaction.
Wherein the amine oxide based oxidizing agent is selected from the group consisting of N-methylmorpholine N-oxide, pyridine N-oxide, trialkyl N-oxide, and mixtures thereof.
In step (b), the oxidation reaction is carried out in a polar aprotic solvent.
Wherein in step (b), the reaction temperature of the oxidation reaction is from 0 캜 to 50 캜.
Wherein in step (b), the reaction time of the oxidation reaction is from 0.5 to 48 hours.
Step (c) In the production method characterized by using an oxidizing agent selected from the group consisting of NaClO 2, NaOCl, hydrogen peroxide, and mixtures thereof in the oxidation reaction.
In step (c), the manufacturing method characterized in that said oxidation reaction carried out in the sulfamic acid (sulfamic acid), DMSO, KH 2 PO 4, NaH 2 PO 4 , or the presence of a mixture thereof.
Wherein in step (c), the reaction temperature of the oxidation reaction is from 0 캜 to 50 캜.
[Chemical Formula 1]
(b) oxidizing the compound of formula (3) to obtain a compound of formula (2); And
(c) oxidizing the compound of Formula 2 to obtain a compound of Formula 1; And
(d) a step of chlorinating the compound of formula (1).
[Chemical Formula 1]
(2)
(3)
[Chemical Formula 4]
[Chemical Formula 5]
Wherein X is halogen; Z is halogen or hydroxy.
Wherein a chlorinating agent selected from the group consisting of SOCl 2 , POCl 3 , oxalyl chloride, PCl 3 , PCl 5 and mixtures thereof is used for the chlorination reaction.
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