CN113788837B - Trilaciclib synthesis method - Google Patents
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Abstract
The application relates to the technical field of synthetic chemistry, in particular to a synthetic method of Trilaciclib. The synthesis method comprises the following steps: carrying out condensation reaction on 2- (methylthio) -7H-pyrrole [2,3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol to obtain an intermediate 1 shown as a formula I: carrying out internal cyclization reaction on the intermediate 1 to obtain an intermediate 2 shown in a formula II; and (3) carrying out nucleophilic substitution reaction on the intermediate 2 and 1-methyl-4- (6-aminopyridine-3-yl) piperazine to obtain the Trilaciclib. Compared with the existing method, the synthesis method obviously shortens the synthesis route and improves the total yield, so the synthesis method has good application prospect in the field of Trilaciclib preparation.
Description
Technical Field
The application belongs to the technical field of synthetic chemistry, and particularly relates to a synthetic method of Trilaciclib.
Background
On the market, at 2 months 2021, the Food and Drug Administration (FDA) approved a new CDK4/6 inhibitor, costela (trilaciclib), a drug that was assigned to the G1 Therapeutics company, a drug that reduced the myelosuppression that occurs in patients with extensive small cell cancer who received some type of chemotherapy, and a first CDK4/6 inhibitor approved for this indication. Cosela (Trilaciclib) can protect bone marrow cells from damage caused by chemotherapy by inhibiting the activity of target CDK4/6, and is a short-acting CDK4/6 inhibitor, and a patient can use the inhibitor before receiving chemotherapy to ensure that the bone marrow stem cells generate short-term cell cycle arrest, so that the bone marrow stem cells are protected from the damage of chemotherapeutic drugs.
The structural formula of Trilaciclib is as follows, and the Cas number of its free base is: 1374743-00-6;
at present, the synthesis of the Trilaciclib can adopt a method developed by the original research company G1 Therapeutics company: taking 4-chloro-2-methylthio pyrimidine-5-carboxylic acid ethyl ester as an initial raw material, and carrying out nucleophilic substitution, Boc protection of an amide group, intramolecular cyclization, Ts on phenolic hydroxyl, OTs removal, thioether oxidation and Boc removal to obtain a methylsulfonyl pyrimidopyrrole derivative, wherein the methylsulfonyl pyrimidopyrrole derivative and 1-methyl-4- (6-aminopyridin-3-yl) piperazine undergo nucleophilic substitution reaction under the action of strong alkali to obtain a final product Trilaciclib; and (II) taking 2, 4-dichloro-5-bromopyrimidine as an initial raw material, and performing nucleophilic substitution, Sonogashira reaction, intramolecular cyclization, acetal deprotection, aldehyde oxidation to acid, protecting group removal of Boc, intramolecular amidation to obtain chloropyrimidino-pyrrole derivatives, wherein the chloropyrimidino-pyrrole derivatives and 1-methyl-4- (6-aminopyridin-3-yl) piperazine perform nucleophilic substitution reaction under the action of strong alkali to obtain the final product Trilaciclib. The two synthetic methods have longer process route and lower total yield.
Disclosure of Invention
The application aims to provide a synthesis method of Trilaciclib, and aims to solve the technical problems of long synthesis route and low yield of the Trilaciclib.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
the application provides a synthesis method of Trilaciclib, which comprises the following steps:
carrying out condensation reaction on 2- (methylthio) -7H-pyrrole [2,3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol to obtain an intermediate 1 shown as a formula I:
carrying out an internal cyclization reaction on the intermediate 1 to obtain an intermediate 2 shown in a formula II;
carrying out nucleophilic substitution reaction on the intermediate 2 and 1-methyl-4- (6-aminopyridine-3-yl) piperazine to obtain Trilaciclib;
according to the synthesis method of Trilaciclib, 2- (methylthio) -7H-pyrrole [2,3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol are used as raw materials, condensation reaction is carried out to obtain an intermediate 1, then intramolecular cyclization is carried out on the intermediate 1 to obtain an intermediate 2, and finally the intermediate 2 and 1-methyl-4- (6-aminopyridin-3-yl) piperazine react to obtain Trilaciclib; compared with the existing method, the synthesis method obviously shortens the synthesis route and improves the total yield, so the synthesis method has good application prospect in the field of Trilaciclib preparation.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
In this application, the term "and/or" describes an association relationship of associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a is present alone, A and B are present simultaneously, and B is present alone. Wherein A and B can be singular or plural. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the present application, "at least one" means one or more, "plural" means two or more. "at least one of the following" or similar expressions refer to any combination of these items, including any combination of the singular or plural items.
It should be understood that, in various embodiments of the present application, the sequence numbers of the above-mentioned processes do not mean the execution sequence, some or all of the steps may be executed in parallel or executed sequentially, and the execution sequence of each process should be determined by its function and inherent logic, and should not constitute any limitation to the implementation process of the embodiments of the present application.
The terminology used in the embodiments of the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in the examples of this application and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weight of the related components mentioned in the description of the embodiments of the present application may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the description of the embodiments of the present application as long as it is scaled up or down according to the description of the embodiments of the present application. Specifically, the mass described in the specification of the embodiments of the present application may be a mass unit known in the chemical industry field such as μ g, mg, g, kg, etc.
The terms "first" and "second" are used for descriptive purposes only and are used for distinguishing purposes such as substances from one another, and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. For example, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX, without departing from the scope of embodiments of the present application. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature.
The meanings of the abbreviations used in the examples of the present application are listed in the following table:
TABLE 1
The embodiment of the application provides a synthesis method of Trilaciclib, which comprises the following steps:
s01: carrying out condensation reaction on 2- (methylthio) -7H-pyrrole [2,3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol serving as raw materials to obtain an intermediate 1 shown in a formula I:
s02: carrying out internal cyclization reaction on the intermediate 1 to obtain an intermediate 2 shown in a formula II;
s03: carrying out nucleophilic substitution reaction on the intermediate 2 and 1-methyl-4- (6-aminopyridine-3-yl) piperazine to obtain Trilaciclib;
the specific route of the Trilaciclib synthesis method provided by the embodiment of the application is as follows, 2- (methylthio) -7H-pyrrole [2,3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol are used as raw materials, a synthesis reaction is carried out to obtain an intermediate 1, then the intermediate 1 is subjected to intramolecular cyclization to obtain an intermediate 2, and finally the intermediate 2 is reacted with 1-methyl-4- (6-aminopyridin-3-yl) piperazine to obtain Trilaciclib; compared with the existing method, the synthesis method of the embodiment obviously shortens the synthesis route and improves the total yield, so the synthesis method has good application prospect in the field of Trilaciclib preparation.
In step S01: specifically, the condensation reaction is carried out under the condition of a condensing agent to condense 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol by the action of the condensing agent to obtain intermediate 1 represented by formula II. Wherein the condensing agent is selected from one or more of HOBt, EDC.HCl, HATU, DCC, DIC, DIPEA, HBTU, HOAt, HOBt, PyBOP, PyAOP, TBTU and BTC; further, a preferred condensing agent is a combination of HOBt and edc.hcl.
The condensation reaction may be carried out in a first solvent, specifically, the first solvent is selected from one or more of N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, toluene, and dichloromethane. The temperature of the condensation reaction is-80 ℃ to 200 ℃, specifically 0 ℃ to 200 ℃, or 50 ℃ to 200 ℃, further the temperature of the condensation reaction can be 100 ℃ to 150 ℃, and the reaction time can be 10 hours to 25 hours.
In one embodiment, the condensation reaction comprises the following steps: 2- (methylthio) -7H-pyrrole [2,3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol are dissolved in a first solvent, and then the above-mentioned condensing agent is added to conduct condensation reaction under the above-mentioned temperature condition.
In step S02: and (3) carrying out intramolecular cyclization reaction on the intermediate 1, specifically, carrying out the intramolecular cyclization reaction under the condition of a catalyst to obtain an intermediate 2 shown in a formula II through catalysis of intramolecular cyclization by the catalyst. Wherein the catalyst is selected from PPh 3 、PMe 3 、ADDP、DEAD、DIAD、CMMP、CMBP、PhSiH 3 、PhI(OAc) 2 One or more of (a).
The internal cyclization reaction can be carried out in a second solvent, specifically, the second solvent is selected from one or more of N, N-dimethylformamide, hexafluoroisopropanol, trifluoroacetic acid, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, toluene and dichloromethane. The temperature of the internal cyclization reaction is-30 ℃ to 220 ℃, specifically, the temperature can be 0 ℃ to 220 ℃, or 50 ℃ to 220 ℃, further, the temperature of the internal cyclization reaction can be 100 ℃ to 160 ℃, and the reaction time can be 20 hours to 35 hours.
In one embodiment, the specific steps of the above-mentioned internal cyclization reaction include: dissolving the intermediate 1 in a second solvent, adding the catalyst, and carrying out catalytic internal cyclization reaction under the temperature condition.
In step S03: in the step of generating the Trilaciclib, the intermediate 2 and 1-methyl-4- (6-aminopyridine-3-yl) piperazine are subjected to nucleophilic substitution reaction to obtain a target product Trilaciclib. Specifically, the nucleophilic substitution reaction is carried out under high temperature solvent-free conditions.
The temperature of the nucleophilic substitution reaction is 80-300 ℃, and specifically can be 100-300 ℃ or 200-300 ℃. Furthermore, the temperature of nucleophilic substitution reaction is 200-250 ℃, and the reaction time is 1-4 h.
In one embodiment, the above nucleophilic substitution reaction comprises the following specific steps: the intermediate 2 and 1-methyl-4- (6-aminopyridin-3-yl) piperazine are mixed in a vacuum tube and then reacted under the temperature conditions. And after the reaction is finished, sequentially washing the reaction product by using water and saturated saline, drying, filtering and removing the solvent to obtain the target product Trilaciclib.
The following description will be given with reference to specific examples.
Example 1
Preparation of intermediate 1 of formula I
A500 mL three-necked flask was charged with 150mL of DMF, 150mL of DCM, 21g (100mmoL) of 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid, 14.3g (110mmoL) of 1-aminomethyl-1-cyclohexanol, 15.2g (100mmoL) of HOBt, and 19.2g (100mmoL) of EDC.HCl in that order, and reacted at 100 ℃ for 20 hours. After the reaction is finished, adding 1N diluted sodium bicarbonate into the system, adjusting the pH value to be 7-8, extracting with DCM, combining organic phases, washing the organic phases with saturated saline water, drying with anhydrous magnesium sulfate, and concentrating the obtained filtrate under reduced pressure to obtain a brown crude product. 300mL of isopropanol was added to the crude product to recrystallize and 25.7g of an off-white solid product was obtained, i.e., intermediate 1, purity 99%, yield 85%.
The structure of the obtained product is confirmed by mass spectrum and nuclear magnetic resonance, and the result is as follows: 1 H NMR(400MHz,DMSO-d 6 )δ1.30-1.65(m,10H),2.48(s,3H),3.10(d,2H),7.11(s,1H),8.81(s,1H),11.90(br,1H).LCMS(ESI):[M+H + ]321.42.
example 2
Preparation of intermediate 1 of formula I
A500 mL three-necked flask was charged with 150mL of DMF, 150mL of DCM, 21g (100mmoL) of 2- (methylthio) -7H-pyrrolo [2,3-d ] pyrimidine-6-carboxylic acid, 14.3g (110mmoL) of 1-aminomethyl-1-cyclohexanol, 32.1g (100mmoL) of TBTU, and 12.9g (100mmoL) of DIPEA in this order, and reacted at 120 ℃ for 20 hours. After the reaction is finished, adding 1N diluted sodium bicarbonate into the system, adjusting the pH value to be 7-8, extracting with DCM, combining organic phases, washing the organic phases with saturated saline water, drying with anhydrous magnesium sulfate, and concentrating the obtained filtrate under reduced pressure to obtain a brown crude product. 320mL of isopropanol is added into the obtained crude product for recrystallization, and 25.4g of off-white solid product is obtained, namely the intermediate 1 with the purity of 99% and the yield of 84%.
Example 3
Preparation of intermediate 2 of formula II
Intermediate 1(25.7g, 80mmoL) and a tetrahydrofuran-toluene mixed solvent (volume ratio 1: 2, total 120mL) were added to a 500mL three-necked flask, CMBP (38.6g,160mmoL) was added dropwise at 0 ℃ and stirred for 30min, and then heated to 150 ℃ to react for 35 hours. After the reaction, a saturated citric acid solution was added, the pH was adjusted to 7.5, the organic phase of the system was separated, the aqueous phase was extracted with toluene (80 mL. times.3 times), the organic phases were combined, washed with saturated brine (120mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give 22g of a yellow viscous crude product. This crude product was dissolved in hot isopropyl ether and then added dropwise to ice-n-hexane, and after a white solid appeared, it was immediately filtered, washed several times with n-hexane and dried to give intermediate 2(21.1g) as a white pure product with a purity of 95% and a yield of 87%.
The structure of the obtained product is confirmed by mass spectrum and nuclear magnetic resonance, and the result is as follows: 1 H NMR(400MHz,DMSO-d 6 )δ1.31-1.70(m,10H),2.47(s,3H),3.15(d,2H),7.10(s,1H),8.90(s,1H).LCMS(ESI):[M+H + ]303.40.
example 4
Preparation of intermediate 2 of formula II
Intermediate 1(25.7g, 80mmoL) and tetrahydrofuran-toluene mixed solvent (volume ratio 1: 2, total 120mL) were added to a 500mL three-necked flask, and CMMP (18.4g,160mmoL), PhSiH, was added dropwise at 0 deg.C 3 (17.3g,160mmoL), stirred for 30min, then warmed to 160 ℃ and reacted for 35 hours. After the reaction, a saturated citric acid solution was added, the pH was adjusted to 7.5, the organic phase of the system was separated, the aqueous phase was extracted with toluene (80 mL. times.3 times), the organic phases were combined, washed with saturated brine (120mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give 22g of a yellow viscous crude product. This crude product was dissolved in hot isopropyl ether and then added dropwise to ice-n-hexane, and after a white solid appeared, it was immediately filtered, washed several times with n-hexane and dried to give a white pure intermediate 2(20.6g) with a purity of 95% and a yield of 85%.
Example 5
Preparation of Trilaciclib
Intermediate 2(21.1g,70mmoL) and 1-methyl-4- (6-aminopyridin-3-yl) piperazine (13.4g,70mmoL) were added to a 100mL vacuum tube and reacted at 230 ℃ for 3 h. After the reaction was completed, 300mL of ethyl acetate was added, and the mixture was washed with water (120mL) and saturated brine (120mL) in this order, dried over anhydrous sodium sulfate and filtered, the resulting solution was evaporated under reduced pressure to remove the solvent, and the obtained residue was recrystallized from ethanol to give Trilaciclib27.5g, purity 99%, and yield 88%.
The structure of the obtained product is confirmed by mass spectrum and nuclear magnetic resonance, and the result is as follows: 1 H NMR(400MHz,DMSO-d 6 )δ1.27-1.44(m,10H)，1.79-1.87(m,5H),2.62-2.69(m,2H),3.16-3.36(m,4H),3.63-3.73(m，2H),7.11(s,1H),7.30(d,1H),7.69(d,1H),7.87(dd,1H),8.81(s,1H).LCMS(ESI)(M+H)447.
the above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (5)
1. A synthesis method of Trilaciclib is characterized by comprising the following steps:
carrying out condensation reaction on 2- (methylthio) -7H-pyrrole [2,3-d ] pyrimidine-6-carboxylic acid and 1-aminomethyl-1-cyclohexanol to obtain an intermediate 1 shown as a formula I:
carrying out an internal cyclization reaction on the intermediate 1 to obtain an intermediate 2 shown in a formula II;
carrying out nucleophilic substitution reaction on the intermediate 2 and 1-methyl-4- (6-aminopyridine-3-yl) piperazine to obtain Trilaciclib shown in a formula III;
the condensation reaction is carried out under the condition of a condensing agent, and the condensing agent is selected from 1-hydroxybenzotriazole, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 2- (7-azobenzotriazol) -N, N, N ', N ' -tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, N, N ' -diisopropylcarbodiimide, N, N-diisopropylethylamine, benzotriazol-N, N, N ', N ' -tetramethylurea hexafluorophosphate, 1-hydroxy-7-azobenzotriazol, 1-hydroxybenzotriazole, benzotriazol-1-yl-oxytripyrrolidinyl hexafluorophosphate, (3H-1,2, 3-triazolo [4 ], 5-b ] pyridine-3-oxy) tri-1-pyrrolidinylphosphonium hexafluorophosphate, O-benzotriazole-N, N, N ', N' -tetramethyluronium tetrafluoroborate and triphosgene, wherein the condensation reaction temperature is 50-200 ℃;
the internal cyclization reaction is carried out under the condition of a catalyst, the catalyst is selected from one or more of triphenylphosphine, trimethylphosphine, azodicarbonyl dipiperidine, diethyl azodicarboxylate, diisopropyl azodicarboxylate, cyanomethylene trimethylphosphine, cyanomethylene tri-n-butylphosphine, phenylsilane and iodobenzene acetate, and the temperature of the internal cyclization reaction is 50-220 ℃;
the temperature of the nucleophilic substitution reaction is 80-300 ℃.
2. The method of synthesis of claim 1, wherein the condensing agent is selected from the group consisting of 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride.
3. The synthetic method of claim 1 wherein the condensation reaction is carried out in a first solvent selected from one or more of N, N-dimethylformamide, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, toluene, and methylene chloride.
4. The synthetic method of claim 1 wherein the internal cyclization reaction is carried out in a second solvent selected from one or more of N, N-dimethylformamide, hexafluoroisopropanol, trifluoroacetic acid, tetrahydrofuran, 2-methyltetrahydrofuran, acetone, 1, 4-dioxane, acetonitrile, toluene, and dichloromethane.
5. The method of synthesis according to any one of claims 1 to 4, wherein the nucleophilic substitution reaction is carried out in the absence of a solvent.
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