CN106565611A - Preparation method for 1-(4-cyclopentylamine-2-methylmercapto-pyrimidine-5-)ethyl ketone - Google Patents
Preparation method for 1-(4-cyclopentylamine-2-methylmercapto-pyrimidine-5-)ethyl ketone Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
Abstract
The invention discloses a preparation method for 1-(4-cyclopentylamine-2-methylmercapto-pyrimidine-5-)ethyl ketone. The method comprises the following steps of: (a) adding 4-cyclopentylamine-2-methylmercapto-pyrimidine-5-ethyl formate disclosed by a formula (1) and alkali into organic solvent to react to obtain 4-cyclopentylamine-2-methylmercapto-pyrimidine-5-methanoic acid disclosed in a formula (2); (b) carrying out condensation reaction on the 4-cyclopentylamine-2-methylmercapto-pyrimidine-5-methanoic acid disclosed in the formula (2) and N,O-dimethylhydroxylamine hydrochloride disclosed in a formula (3) to obtain a 4-cyclopentylamine-N-methoxyl-N-methyl-2-methylmercapto-pyrimidine-5-formamide disclosed in a formula (4); and (c) enabling the 4-cyclopentylamine-N-methoxyl-N-methyl-2-methylmercapto-pyrimidine-5-formamide disclosed in the formula (4) to react with methyl magnesium bromide to obtain the1-(4-cyclopentylamine-2-methylmercapto-pyrimidine-5-)ethyl ketone disclosed in a formula (5). The preparation method disclosed by the invention has the advantages of being low in cost and convenient and safe in operation and is easy in large-scale industrial production, and column chromatography isolation purification is not required during postprocessing.
Description
Technical field
The invention belongs to pharmaceutical synthesis chemical technology field, and in particular to a kind of preparation method for synthesizing intermediate 1- (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) the base ethyl ketone of Pabuk former times profit cloth.
Background technology
Pabuk former times profit cloth (Palbociclib) is the adopted name of 6- acetyl group -8- cyclopenta -5- methyl -2- [[5- (piperazine -1- bases) pyridine -2- bases] amino] -8H- pyridos [2,3-D] pyrimidin-7-ones, and its structural formula is：
Pabuk former times profit cloth is first cell cycle protein dependent kinase 4/6 (CDK4/6) inhibitor of FDA approvals, can be with letrozole use in conjunction as the first-line drug for treating the ER positives/HER2 feminine gender post menopausal metastatic breast cancers, clinical research shows, Palbociclib joint letrozoles can bring up to the middle position of patient with breast cancer 26.1 months without disease life cycle (PFS), therefore the medicine has wide application scenario.
Patent WO 2012/068381 reports a kind of preparation method of intermediate 1- (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) the base ethyl ketone of Pabuk former times profit cloth, the method uses the Lithium Aluminium Hydride with irritating manganese dioxide and with strong reducing property in preparation process, it is relatively costly, and the method needs to use column chromatographic isolation and purification product in post processing, is unsuitable for industrialized production.
The content of the invention
In order to overcome drawbacks described above of the prior art, the present invention proposes a kind of method prepared for synthesizing intermediate 1- (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) the base ethyl ketone of Pabuk former times profit cloth, the preparation method of the present invention is with low cost, it is easy to operate and safe, it is easy to large-scale industrial production.
Intermediate 1- (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) the base ethyl ketone that can be prepared the present invention synthesizes Pabuk former times profit cloth by multistep reactions such as oxidation, coupling, hydrolysis, deprotections.
Route (1).
The present invention proposes a kind of preparation method of 1- (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethyl ketone, it is characterised in that the method comprising the steps of：
A 4- Aminocyclopentanes base -2- methylthiopyrimidine -5- Ethyl formates shown in () with formula (1) prepare -2- methylthiopyrimidine -5- formic acid of 4- Aminocyclopentanes base shown in formula (2) as raw material；
B 4- Aminocyclopentanes base -2- methylthiopyrimidine -5- formic acid shown in () formula (2) and N shown in formula (3), O- dimethyl hydroxylamine hydrochlorides are condensed to yield the-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- Methanamides of 4- Aminocyclopentanes base shown in formula (4)；
C-the N- of 4- Aminocyclopentanes base shown in () formula (4) methoxy-. N-methyl -2- methylthiopyrimidine -5- Methanamides obtain 1- shown in formula (5) (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethyl ketone with methyl bromide reactive magnesium；
Wherein, in the step (a), alkali and the -2- methylthiopyrimidine -5- Ethyl formates of 4- Aminocyclopentanes base shown in formula (1) are added in organic solvent and are reacted, obtain -2- methylthiopyrimidine -5- the formic acid of 4- Aminocyclopentanes base shown in formula (2).
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 temperatures.
Wherein, the mol ratio of the inventory is 4- Aminocyclopentane base -2- methylthiopyrimidine -5- Ethyl formates：Alkali=1:1.5～2.5；The consumption of the organic solvent is 5～10 times of the quality of the 4- Aminocyclopentanes base -2- methylthiopyrimidine -5- Ethyl formates.
Wherein, in the step (b), formula (2) the 4- Aminocyclopentanes base -2- methylthiopyrimidines -5- formic acid is dissolved in organic solvent, sequentially add alkali and condensing agent, 10～30min of stirring, N shown in addition formula (3), O- dimethyl hydroxylamine hydrochlorides reaction, obtains-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- the Methanamides of 4- Aminocyclopentanes base shown in formula (4).
Wherein, the condensing agent is EDCI, HBTU, HOBt or CDI；The alkali is DIPEA, TEA or pyridine；The organic solvent is DMF, DCM or THF.
Wherein, 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.
Wherein, in the step (c);-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- the Methanamides of 4- Aminocyclopentanes base shown in formula (4) are dissolved in tetrahydrofuran; under nitrogen protection; the tetrahydrofuran solution reaction of Deca methyl-magnesium-bromide, obtains 1- shown in formula (5) (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethyl ketone.
Wherein, the mol ratio of the inventory is 4- Aminocyclopentanes base-N- methoxy-. N-methyls -2- methylthiopyrimidines -5- Methanamides (4)：Methyl-magnesium-bromide=1:2.0～3.0.
Specifically, a kind of preparation method of intermediate 1- (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) the base ethyl ketone of Pabuk former times profit cloth is, -2- methylthiopyrimidine -5- the formic acid of 4- Aminocyclopentanes base shown in formula (2) is obtained by raw material of 4- Aminocyclopentanes base -2- methylthiopyrimidine -5- Ethyl formates shown in formula (1) through hydrolysis, then again with N shown in formula (3), O- dimethyl hydroxylamine hydrochlorides are condensed to yield the -2- methylthiopyrimidine -5- Methanamides of 4- Aminocyclopentanes base shown in formula (4), finally obtaining target product 1- shown in formula (5) (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethyl ketone with methyl bromide reactive magnesium.Concrete technology is carried out by following three step
The first step, -2- methylthiopyrimidine -5- Ethyl formates of 4- Aminocyclopentanes base shown in formula (1) are hydrolyzed in the presence of alkali and obtain -2- methylthiopyrimidine -5- the formic acid of 4- Aminocyclopentanes base shown in formula (2)；
First alkali is configured to into the aqueous slkali that mass fraction is 5%～40%, it is cooled to room temperature, organic solvent and the -2- methylthiopyrimidine -5- Ethyl formates of 4- Aminocyclopentanes base shown in formula (1) are added in aqueous slkali, react 5～7 hours under room temperature, THF is removed in rotation, it is 5～6 to adjust pH value with hydrochloric acid, and through filtering and washing drying the base -2- methylthiopyrimidine -5- formic acid of white solid 4- Aminocyclopentanes shown in formula (2) is being obtained；
The mol ratio of the inventory is 4- Aminocyclopentane base -2- methylthiopyrimidine -5- Ethyl formates：Alkali=1:1.5～2.5；
The organic solvent is ethanol or tetrahydrofuran, and consumption is 5～10 times of the quality of 4- Aminocyclopentane base -2- methylthiopyrimidine -5- Ethyl formates；Alkali is sodium hydroxide or potassium hydroxide；
Second step, 4- Aminocyclopentanes base -2- methylthiopyrimidine -5- formic acid shown in formula (2) and N shown in formula (3), O- dimethyl hydroxylamine hydrochlorides are through being condensed to yield-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- the Methanamides of 4- Aminocyclopentanes base shown in formula (4)；
- 2- methylthiopyrimidine -5- the formic acid of 4- Aminocyclopentanes base shown in formula (2) is dissolved in the organic solvent of 5～10 times of volumes, sequentially add alkali and condensing agent, 10～30min of stirring, N shown in addition formula (3), O- dimethyl hydroxylamine hydrochlorides, react 4～6 hours under room temperature, after extraction, washing, concentration the-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- Methanamides of 4- Aminocyclopentanes base shown in pale yellow oil formula (4) are obtained；
The condensing agent is EDCI, HBTU, HOBt or CDI；The alkali is DIPEA, TEA or pyridine；The organic solvent is DMF, DCM or THF；
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；
3rd step, 4- Aminocyclopentanes base-N- methoxy-. N-methyls -2- methylthiopyrimidines -5- Methanamides (4) shown in formula (4) obtain 1- shown in formula (5) (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethyl ketone with methyl bromide reactive magnesium；
- N- methoxy-. N-methyl -2- methylthiopyrimidine -5- the Methanamides of 4- Aminocyclopentanes base shown in formula (4) are dissolved in the tetrahydrofuran of 5～10 times of volumes; it is cooled to 0 DEG C; under nitrogen protection; the tetrahydrofuran solution of Deca methyl-magnesium-bromide; 2～4 hours Deca saturated aqueous ammonium chlorides are reacted at 0～10 DEG C reaction is quenched; rotation goes after THF to add ethyl acetate and water extraction, then through washing, being concentrated to give faint yellow solid 1- shown in formula (5) (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethyl ketone；
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.
Involved technical term：
Table 1
| Abbreviation | Explanation |
| EDCI | 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate |
| HBTU | O- BTAs-tetramethylurea hexafluorophosphate |
| HOBt | I-hydroxybenzotriazole |
| CDI | N, N'- carbonyl dimidazoles |
| DIPEA | DIPEA |
| TEA | Triethylamine |
| DMF | N,N-dimethylformamide |
| DCM | Dichloromethane |
| THF | Tetrahydrofuran |
The beneficial effects of the present invention is：
The invention discloses the method that one kind sequentially passes through hydrolysis with 4- Aminocyclopentane base -2- methylthiopyrimidines -5- bases Ethyl formates as raw material, condensation, methylation reaction prepare 1- (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethyl ketone.
1. in the last handling process of the preparation method of the present invention, without the need for column chromatographic isolation and purification, operating procedure is simplified, be suitable to industrialization large-scale production.
2. present invention, avoiding using the lithium aluminium hydride reduction of strong reducing property and with irritating manganese dioxide, easy to operate and safe, agents useful for same low price is easy to get, and reduces production cost, be adapted to large-scale industrial production..
3. the product 4- Aminocyclopentane base -2- methylthiopyrimidine -5- ethyl ketone Jing subsequent reactions that the present invention is obtained can obtain end-product Pabuk former times profit cloth, therefore the preparation method of the Pabuk former times profit cloth important intermediate of the present invention has economic and social benefit.
Specific embodiment
With reference to specific examples below, the present invention is described in further detail.Implement process, condition, experimental technique of the present invention etc., in addition to the following content for specially referring to, be the universal knowledege and common knowledge of this area, the present invention is not particularly limited content.
Embodiment 1
The synthesis of -2- methylthiopyrimidine -5- the carboxylic acid compounds of 4- Aminocyclopentanes base shown in formula (2)
By NaOH (15.1g, 378mmol) and 250ml water wiring solution-formings, room temperature is cooled to.By raw material 4- Aminocyclopentane base -2- methylthiopyrimidine -5- Ethyl formate (53g, in 189mmol) being added to 1000ml three-necked bottles, 250ml ethanol and the NaOH solution matched somebody with somebody above are added thereto to again, react 6.5 hours under room temperature, vacuum rotary steam is to 250ml, Deca 6mol/L hydrochloric acid 64ml, it is 5 to adjust pH value, there are a large amount of white solids to separate out, sucking filtration obtains white solid, precipitated with 2 × 50ml water washings, drying obtains target product 4- Aminocyclopentane base -2- methylthiopyrimidine -5- formic acid (2) 47.5g, yield 99.5%.
1H NMR (400MHz, DMSO) δ 13.24 (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).
The synthesis of-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- the benzamide compounds of 4- Aminocyclopentanes base shown in formula (4)
By 4- Aminocyclopentane base -2- methylthiopyrimidine -5- formic acid (25.3g，In 100mmol) being added to 1000ml three-necked bottles，Add DIPEA (70ml，400mmol) with 300ml dichloromethane，Stir 15min under room temperature to be completely dissolved to solid，Sequentially add HBTU (56.9g，150mmol) with HOBt (20.3g，150mmol)，N is added after stirring 30min,O- dimethyl hydroxylamine hydrochloride (14.6g，150mmol)，React 5 hours under room temperature，Add water in system and carry out a point liquid after 300ml，Organic faciess are washed respectively with 100ml water and 100ml saturated aqueous common salts，Organic faciess vacuum rotary steam obtains pale yellow oil 29.1g to dry，Yield 98.3%.
1H NMR(400MHz,CDCl3) δ 8.55 (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).
The synthesis of 1- shown in formula (5) (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethanone compounds
By 4- Aminocyclopentane base-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- Methanamide (21.5g, in 72.6mmol) being added to 500ml three-necked bottles, add 150ml tetrahydrofurans, it is cooled to 0 DEG C, under nitrogen protection, methyl-magnesium-bromide tetrahydrofuran solution (the 218ml of Deca 1mol/L, 218mmol), react 2 hours at 0 DEG C, add 50ml saturated aqueous ammonium chlorides that reaction is quenched, vacuum rotary steam is to 100ml, adding 300ml ethyl acetate and 100ml carries out moisture liquid, organic faciess 100ml water and 100ml saturated common salt water washings, organic faciess are spin-dried for obtaining yellow solid 16.8g, yield 92%.
1H NMR(400MHz,CDCl3) δ 9.23 (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).
Embodiment 2
The synthesis of -2- methylthiopyrimidine -5- the carboxylic acid compounds of 4- Aminocyclopentanes base shown in formula (2)
By NaOH (1.45g, 35.6mmol) and 20ml water wiring solution-formings, room temperature is cooled to.By raw material 4- Aminocyclopentane base -2- methylthiopyrimidine -5- Ethyl formate (5g, in 17.8mmol) being added to 100ml three-necked bottles, 30ml ethanol and the NaOH solution matched somebody with somebody above are added thereto to again, react 4 hours under room temperature, vacuum rotary steam is to 20ml, Deca 6mol/L hydrochloric acid 6ml, pH value is 5, there are a large amount of white solids to produce, sucking filtration obtains white solid, precipitated with 2 × 10ml water washings, drying obtains target product 4- Aminocyclopentane base -2- methylthiopyrimidine -5- formic acid (2) 4.45g, yield 98.8%.
The synthesis of-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- the benzamide compounds of 4- Aminocyclopentanes base shown in formula (4)
By 4- Aminocyclopentane base -2- methylthiopyrimidine -5- formic acid (0.5g, in 1.98mmol) being added to 25ml single port bottles, add DIPEA (1.4ml, 7.9mmol) with 5ml DMF, stir 5min under room temperature to be completely dissolved to solid, sequentially add HBTU (1.14g, 2.96mmol), N is added after stirring 30min, O- dimethyl hydroxylamine hydrochloride (0.295g, 2.96mmol), react 5 hours under room temperature, a point liquid is carried out after 20ml ethyl acetate 60ml that adds water in system, organic faciess are successively with 20ml water and 20ml saturated common salt water washings, organic faciess vacuum rotary steam obtains pale yellow oil 0.56g to dry, yield 95.7%.
The synthesis of 1- shown in formula (5) (4- Aminocyclopentane base -2- methylthiopyrimidine -5-) base ethanone compounds
By 4- Aminocyclopentane base-N- methoxy-. N-methyl -2- methylthiopyrimidine -5- Methanamide (0.59g; in 2mmol) being added to 50ml three-necked bottles; add 6ml tetrahydrofurans; it is cooled to 0 DEG C; under nitrogen protection; methyl-magnesium-bromide tetrahydrofuran solution (the 6ml of Deca 1mol/L; 6mmol); react 1.5 hours at 0 DEG C; add 2ml saturated sodium bicarbonate aqueous solutions that reaction is quenched, point liquid, organic faciess 5ml water and 5ml saturated common salt water washings; organic faciess are spin-dried for obtaining yellow solid 0.46g, yield 90.5%.
The protection content of the present invention is not limited to above example.Under the spirit and scope without departing substantially from inventive concept, those skilled in the art it is conceivable that change and advantage be all included in the present invention, and with appending claims as protection domain.
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.
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| CN108503581A (en) * | 2018-04-12 | 2018-09-07 | 苏州康润医药有限公司 | A kind of synthetic method of the fluoro- 2- pyridines ethyl ketones of the bromo- 6- of 3- |
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