CN106565611A - Preparation method for 1-(4-cyclopentylamine-2-methylmercapto-pyrimidine-5-)ethyl ketone - Google Patents

Abstract

The invention discloses a preparation method of 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)yl ethanone, comprising: (a) 4-cyclopentylamino group represented by formula (1) -2-methylthiopyrimidine-5-formic acid ethyl ester and alkali join in the organic solvent to react, obtain 4-cyclopentylamino-2-methylthiopyrimidine-5-formic acid shown in formula (2); (b) 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid shown in formula (2) is condensed with N,O-dimethylhydroxylamine hydrochloride shown in formula (3) to obtain Show 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide; (c) 4-cyclopentylamino-N-form shown in formula (4) Oxygen-N-methyl-2-methylthiopyrimidine-5-carboxamide reacts with methylmagnesium bromide to obtain 1-(4-cyclopentylamino-2-methylthiopyrimidine shown in formula (5) -5-) ethyl ethyl ketone. The preparation method of the invention is low in cost, simple and safe in operation, does not need column chromatography separation and purification during post-treatment, and is easy for large-scale industrial production.

Description

A kind of preparation method of 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-) base ethyl ketone

technical field

The invention belongs to the technical field of pharmaceutical synthesis and chemical engineering, and in particular relates to a preparation method of 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)ylethanone, an intermediate used in the synthesis of palbociclib .

Background technique

Palbociclib (Palbociclib) is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(piperazin-1-yl)pyridin-2-yl]amino]-8H- Generic name for pyrido[2,3-D]pyrimidin-7-one, whose structural formula is:

Palbociclib, the first FDA-approved cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, can be used in combination with letrozole as first-line treatment for ER-positive/HER2-negative postmenopausal metastatic breast cancer Drugs, clinical studies have shown that Palbociclib combined with letrozole can increase the median disease-free survival (PFS) of breast cancer patients to 26.1 months, so the drug has broad application scenarios.

Patent WO 2012/068381 reports a preparation method of 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)ylethanone, an intermediate of palbociclib, in the preparation process The cost of using irritating manganese dioxide and strong reducing lithium aluminum hydride is relatively high, and this method needs to use column chromatography to separate and purify the product during post-treatment, which is not suitable for industrial production.

Contents of the invention

In order to overcome the above-mentioned defects in the prior art, the present invention proposes a preparation of intermediate 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-) for the synthesis of palbociclib The ketone method, the preparation method of the present invention has low cost, simple and safe operation, and is easy for large-scale industrial production.

The intermediate 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)yl ethanone prepared in the present invention can be synthesized into palbouximil through multi-step reactions such as oxidation, coupling, hydrolysis, and deprotection. Lieb.

Route (1).

The present invention proposes a kind of preparation method of 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-) base ethyl ketone, it is characterized in that, described method comprises the following steps:

(a) 4-cyclopentylamino-2-methylthiopyrimidine-5-formic acid ethyl ester shown in formula (1) is used as raw material to prepare 4-cyclopentylamino-2-methylthio shown in formula (2) Pyrimidine-5-carboxylic acid;

(b) Condensation of 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid represented by formula (2) with N,O-dimethylhydroxylamine hydrochloride represented by formula (3) to obtain formula (4) The shown 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide;

(c) 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-formamide shown in formula (4) reacts with methylmagnesium bromide to obtain formula (5) The shown 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)yl ethanone;

Wherein, in the step (a), the base and ethyl 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylate shown in formula (1) are added to an organic solvent for reaction to obtain formula (2) Shown is 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid.

Wherein, the alkali is sodium hydroxide or potassium hydroxide, and the mass fraction of the alkali is 5%-40%; the organic solvent is ethanol or tetrahydrofuran.

Wherein, the reaction is carried out at normal temperature.

Wherein, the molar ratio of the feeding amount is ethyl 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylate:base=1:1.5～2.5; the amount of the organic solvent is the 4-cyclopentyl 5-10 times the mass of ethyl pentylamino-2-methylthiopyrimidine-5-carboxylate.

Wherein, in the step (b), the 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid described in the formula (2) is dissolved in an organic solvent, and then the alkali and the condensing agent are added successively, and stirred for 10 ~30min, add N,O-dimethylhydroxylamine hydrochloride represented by formula (3) and react to obtain 4-cyclopentylamino-N-methoxy-N-methyl-2- Methylthiopyrimidine-5-carboxamide.

Wherein, the condensing agent is EDCI, HBTU, HOBt or CDI; the base is DIPEA, TEA or pyridine; the organic solvent is DMF, DCM or THF.

Wherein, the molar ratio of the feeding amount is 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid:N,O-dimethylhydroxylamine hydrochloride:condensing agent:base=1:1.1～1.5 :1.1～1.5:2.5～4.

Wherein, in the step (c), 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide shown in formula (4) is dissolved in tetrahydrofuran , under the protection of nitrogen, a tetrahydrofuran solution of methylmagnesium bromide was added dropwise to react to obtain 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)ylethanone shown in formula (5).

Wherein, the molar ratio of said feeding amount is 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide (4): methylmagnesium bromide=1 :2.0～3.0.

Specifically, the preparation method of the intermediate 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)yl ethanone of the palbociclib is as shown in formula (1): 4-cyclopentylamino-2-methylthiopyrimidine-5-formic acid ethyl ester is that raw material obtains 4-cyclopentylamino-2-methylthiopyrimidine-5-formic acid shown in formula (2) through hydrolysis, and then Condensed with N,O-dimethylhydroxylamine hydrochloride shown in formula (3) to obtain 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxamide shown in formula (4), and finally with methyl Magnesium bromide is reacted to obtain the target product 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)ylethanone shown in formula (5). The specific process is carried out in the following three steps

In the first step, 4-cyclopentylamino-2-methylthiopyrimidine-5-formic acid ethyl ester shown in formula (1) is hydrolyzed under the effect of alkali to obtain 4-cyclopentylamino-2 shown in formula (2) - methylthiopyrimidine-5-carboxylic acid;

First configure the base into a base solution with a mass fraction of 5% to 40%, cool to room temperature, and combine the organic solvent and ethyl 4-cyclopentylamino-2-methylthiopyrimidine-5-formate shown in formula (1) Add it into the alkaline solution, react at room temperature for 5-7 hours, spin off THF, adjust the pH value to 5-6 with hydrochloric acid, and obtain the white solid 4-cyclopentylamino group shown in formula (2) after washing with suction and drying. -2-Methylthiopyrimidine-5-carboxylic acid;

The molar ratio of the feeding amount is ethyl 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylate: alkali=1:1.5～2.5;

The organic solvent is ethanol or tetrahydrofuran, and the dosage is 5 to 10 times the mass of ethyl 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylate; the base is sodium hydroxide or potassium hydroxide;

In the second step, 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid shown in formula (2) and N, O-dimethyl hydroxylamine hydrochloride shown in formula (3) are condensed to obtain formula ( 4) The shown 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide;

Dissolve 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid represented by formula (2) in 5 to 10 times the volume of organic solvent, then add alkali and condensing agent in sequence, stir for 10 to 30 minutes, add N,O-dimethylhydroxylamine hydrochloride represented by formula (3), reacted at room temperature for 4 to 6 hours, extracted, washed, and concentrated to obtain a light yellow oily substance represented by formula (4) 4-cyclopentylamino- N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide;

The condensing agent is EDCI, HBTU, HOBt or CDI; the base is DIPEA, TEA or pyridine; the organic solvent is DMF, DCM or THF;

The molar ratio of the feeding amount is 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid:N,O-dimethylhydroxylamine hydrochloride:condensing agent:base=1:1.1～1.5:1.1 ~1.5:2.5~4;

In the third step, 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide (4) shown in formula (4) reacts with methylmagnesium bromide to obtain 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-) base ethyl ketone shown in formula (5);

Dissolve 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide shown in formula (4) in 5 to 10 times the volume of tetrahydrofuran, and cool to 0 ℃, under the protection of nitrogen, dropwise add tetrahydrofuran solution of methylmagnesium bromide, react at 0~10℃ for 2~4 hours, add dropwise saturated ammonium chloride aqueous solution to quench the reaction, spin off THF, add ethyl acetate and water to extract, After washing and concentrating, the light yellow solid 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)yl ethanone shown in formula (5) is obtained;

The molar ratio of the feed amount is 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide:methylmagnesium bromide=1:2.0-3.0.

Technical terms involved:

Table 1

abbreviation illustrate EDCI 1-Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride HBTU O-Benzotriazole-tetramethyluronium hexafluorophosphate HOB 1-Hydroxybenzotriazole CDI N,N'-Carbonyldiimidazole DIPEA N,N-Diisopropylethylamine TEA Triethylamine DMF N,N-Dimethylformamide DCM Dichloromethane THF Tetrahydrofuran

The beneficial effects of the present invention are:

The invention discloses a 1-(4-cyclopentylamino group) prepared from 4-cyclopentylamino-2-methylthiopyrimidin-5-yl formic acid ethyl ester through successive hydrolysis, condensation and methylation reactions. -2-Methylthiopyrimidin-5-) Ethanone method.

1. In the post-treatment process of the preparation method of the present invention, there is no need for column chromatography separation and purification, which simplifies the operation steps and is suitable for large-scale industrial production.

2. The present invention avoids the use of strong reducing lithium aluminum hydride and irritating manganese dioxide, and is easy and safe to operate, and the reagents used are cheap and easy to obtain, which reduces production costs and is suitable for large-scale industrial production. .

3. The product 4-cyclopentylamino-2-methylthiopyrimidine-5-ethanone obtained in the present invention can obtain the final product palbociclib through subsequent reactions, so the important intermediate of palbociclib in the present invention The preparation method has economic and social benefits.

detailed description

In conjunction with the following specific examples, the present invention is further described in detail. The process, conditions, experimental methods, etc. for implementing the present invention, except for the content specifically mentioned below, are common knowledge and common knowledge in this field, and the present invention has no special limitation content.

Example 1

Synthesis of 4-cyclopentylamino-2-methylthiopyrimidine-5-formic acid compound shown in formula (2)

A solution of NaOH (15.1 g, 378 mmol) and 250 ml of water was made and cooled to room temperature. The raw material 4-cyclopentylamino-2-methylthiopyrimidine-5-ethyl carboxylate (53g, 189mmol) was added in a 1000ml three-necked flask, and then 250ml of ethanol and the NaOH solution prepared above were added thereto. React for 6.5 hours, vacuum rotary steam to 250ml, add dropwise 64ml of 6mol/L hydrochloric acid, adjust the pH value to 5, a large amount of white solid precipitates, filter with suction to obtain the white solid, wash the precipitate with 2×50ml of water, and dry to obtain the target product 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid (2) 47.5 g, yield 99.5%.

¹ H NMR (400MHz,DMSO)δ13.24(s,1H),8.51(s,1H),8.39(d,J=6.7Hz,1H),4.45–4.32(m,1H),2.48(s,3H ),2.02(dd,J=12.2,5.6Hz,2H),1.75–1.64(m,2H),1.59(t,J=11.9Hz,2H),1.48(dt,J=12.3,6.2Hz,2H) .

Synthesis of 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide compound shown in formula (4)

4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid (25.3g, 100mmol) was added to a 1000ml three-necked flask, DIPEA (70ml, 400mmol) and 300ml dichloromethane were added, and stirred at room temperature for 15min to The solid was completely dissolved, then added HBTU (56.9g, 150mmol) and HOBt (20.3g, 150mmol) in sequence, and after stirring for 30min, added N,O-dimethylhydroxylamine hydrochloride (14.6g, 150mmol), and reacted for 5 hours at room temperature After adding 300ml of water to the system, the liquid was separated, the organic phase was washed with 100ml of water and 100ml of saturated brine, and the organic phase was rotary evaporated to dryness under reduced pressure to obtain 29.1g of light yellow oil, with a yield of 98.3%.

¹ H NMR (400MHz, CDCl ₃ ) δ8.55(s, 1H), 7.94(t, J=10.0Hz, 1H), 4.49–4.38(m, 1H), 3.62(s, 3H), 3.33(s, 3H),2.53(s,3H),2.12–2.01(m,2H),1.77–1.68(m,2H),1.63(qd,J＝8.9,5.0Hz,2H),1.51(ddd,J＝14.3, 10.2,3.9Hz,2H).

Synthesis of 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)yl ethanone compound shown in formula (5)

Add 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide (21.5g, 72.6mmol) into a 500ml three-necked flask, then add 150ml tetrahydrofuran, Cool to 0°C, under nitrogen protection, add 1mol/L methylmagnesium bromide tetrahydrofuran solution (218ml, 218mmol) dropwise, react at 0°C for 2 hours, add 50ml saturated ammonium chloride aqueous solution to quench the reaction, and rotary evaporate under reduced pressure to 100ml, then add 300ml ethyl acetate and 100ml for water solution, the organic phase was washed with 100ml water and 100ml saturated brine, and the organic phase was spin-dried to obtain 16.8g of a yellow solid with a yield of 92%.

¹ H NMR (400MHz, CDCl ₃ )δ9.23(s,1H),8.54(s,1H),4.57–4.43(m,1H),2.54(s,3H),2.49(s,3H),2.13– 2.02(m,2H),1.78–1.70(m,2H),1.70–1.60(m,2H),1.55(td,J＝13.1,6.6Hz,2H).

Example 2

Synthesis of 4-cyclopentylamino-2-methylthiopyrimidine-5-formic acid compound shown in formula (2)

A solution of NaOH (1.45 g, 35.6 mmol) and 20 ml of water was made and cooled to room temperature. The raw material 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid ethyl ester (5g, 17.8mmol) was added in a 100ml three-necked flask, and then 30ml of ethanol and the NaOH solution prepared above were added thereto, at room temperature React under low pressure for 4 hours, rotary evaporate to 20ml under reduced pressure, add 6ml of 6mol/L hydrochloric acid dropwise, the pH value is 5, a large amount of white solid is produced, the white solid is obtained by suction filtration, the precipitate is washed with 2×10ml of water, and dried to obtain the target product 4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid (2) 4.45 g, yield 98.8%.

Synthesis of 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide compound shown in formula (4)

4-cyclopentylamino-2-methylthiopyrimidine-5-carboxylic acid (0.5g, 1.98mmol) was added to a 25ml single-necked bottle, DIPEA (1.4ml, 7.9mmol) and 5ml DMF were added, and stirred at room temperature for 5min to The solid is completely dissolved, then add HBTU (1.14g, 2.96mmol) in turn, stir for 30min, then add N,O-dimethylhydroxylamine hydrochloride (0.295g, 2.96mmol), react at room temperature for 5 hours, add 20ml of water to the system After 60ml of ethyl acetate, the liquid was separated, and the organic phase was washed successively with 20ml of water and 20ml of saturated brine, and the organic phase was rotary evaporated to dryness under reduced pressure to obtain 0.56g of light yellow oil, with a yield of 95.7%.

Synthesis of 1-(4-cyclopentylamino-2-methylthiopyrimidin-5-)yl ethanone compound shown in formula (5)

Add 4-cyclopentylamino-N-methoxy-N-methyl-2-methylthiopyrimidine-5-carboxamide (0.59g, 2mmol) into a 50ml three-necked flask, then add 6ml tetrahydrofuran, and cool To 0°C, under the protection of nitrogen, add dropwise 1mol/L methylmagnesium bromide tetrahydrofuran solution (6ml, 6mmol), react at 0°C for 1.5 hours, add 2ml saturated aqueous sodium bicarbonate solution to quench the reaction, separate liquid, organic phase Washed with 5 ml of water and 5 ml of saturated brine, the organic phase was spin-dried to obtain 0.46 g of a yellow solid, with a yield of 90.5%.

The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present invention, and the appended claims are the protection scope.

Claims (10)

1. a kind of preparation method of 1- (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethyl ketone, it is characterised in that methods described includes Following steps：

A 4- Aminocyclopentanes base -2- methylthiopyrimidine -5- Ethyl formates shown in () formula (1) and alkali are added to reaction in organic solvent and obtain - 2- methylthiopyrimidine -5- the formic acid of 4- Aminocyclopentanes base shown in formula (2)；

B () is dissolved in -2- methylthiopyrimidine -5- formic acid of 4- Aminocyclopentanes base shown in formula (2) in organic solvent, sequentially add alkali and Condensing agent, stirring adds N shown in formula (3), the reaction of O- dimethyl hydroxylamine hydrochlorides to obtain 4- Aminocyclopentane bases shown in formula (4) - N- methoxy-. N-methyl -2- methylthiopyrimidine -5- Methanamides；

C-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- the Methanamides of 4- Aminocyclopentanes base shown in formula (4) are dissolved in tetrahydrofuran by () In, the tetrahydrofuran solution reaction of Deca methyl-magnesium-bromide obtains 1- shown in formula (5) (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) Base ethyl ketone；

2. preparation method as claimed in claim 1, it is characterised in that in the step (a), the alkali is sodium hydroxide or hydrogen Potassium oxide, the mass fraction of the alkali is 5%～40%；The organic solvent is ethanol or tetrahydrofuran.

3. preparation method as claimed in claim 1, it is characterised in that in the step (a), the reaction is carried out at normal temperatures.

4. preparation method as claimed in claim 1, it is characterised in that in the step (a), the mol ratio of the inventory is 4- Aminocyclopentane base -2- methylthiopyrimidine -5- Ethyl formates：Alkali=1:1.5～2.5.

5. preparation method as claimed in claim 1, it is characterised in that in the step (b), the condensing agent be EDCI, HBTU, HOBt or CDI.

6. preparation method as claimed in claim 1, it is characterised in that in the step (b), the alkali is DIPEA, TEA Or pyridine.

7. preparation method as claimed in claim 1, it is characterised in that in the step (b), the organic solvent be DMF, DCM or THF.

8. preparation method as claimed in claim 1, it is characterised in that in the step (b), the mol ratio of the inventory is 4- Aminocyclopentane base -2- methylthiopyrimidine -5- formic acid：N, O- dimethyl hydroxylamine hydrochloride：Condensing agent：Alkali =1:1.1～1.5:1.1～1.5:2.5～4.

9. preparation method as claimed in claim 1, it is characterised in that in the step (c), the mol ratio of the inventory is 4- Aminocyclopentane base-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- Methanamides：Methyl-magnesium-bromide=1:2.0～3.0.

10. preparation method as claimed in claim 1, it is characterised in that in the step (c), the reaction is under nitrogen protection Carry out.