CN105541832A - Preparation method of Palbociclib isethionate - Google Patents
Preparation method of Palbociclib isethionate Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention belongs to the field of chemical medicine synthesis technology, and more specifically relates to a preparation method of Palbociclib isethionate. The method comprises four steps and is used for preparing Palbociclib, that is 2-(pyridin-2-ylamino)-pyrido[2,3-d]pyrimidin-7-one isethionate. The method has the advantages of mild process conditions, simple post-treatment, high purity, low reaction cost, and easy industrial production.
Description
Technical field
The invention belongs to chemicals synthesis technical field, be specifically related to the preparation method of profit cloth of a kind of isethionate Pabuk former times.
Background technology
Pabuk former times profit cloth (Palbociclib) is a kind of new oral targeting preparation that Pfizer is developed, can Selective depression cell cycle protein dependent kinase 4 and 6 (CDK4/6), recover cell cycle control, block tumor cell proliferation, FDA (U.S. food Drug Administration) authorizes the Palbociclib breakthrough therapy identification for the treatment of late period or transitivity ER+/HER2-mammary cancer in April, 2013.
Female mammary gland is made up of skin, fibrous tissue, corpus mamma and fat, and mammary cancer is the malignant tumour occurring in mammary gland glandular epithelium tissue.In mammary cancer, 99% occurs in women, and the male sex only accounts for 1%.Breast carcinoma of early stage does not often possess typical sings and symptoms, not easily draws attention, and finds usually through health check-up or mammary cancer examination.Be below the typical sign of mammary cancer: 1. mammary gland tumor 2. nipple discharge 3. nipple, the abnormal 4. axillary gland enlargement of mammary areola.The cause of disease of mammary cancer is not yet completely clear, and research finds that the morbidity of mammary cancer exists certain regularity, and the women with high-risk breast cancer factor easily suffers from breast cancer.
1. Hazard Factor and patient features
At the age: 0 ~ 24 years old age place's lower level, rise gradually after 25 years old, within 50 ~ 54 years old, peak, within 55 years old, decline gradually later.
Family history: epidemiology survey finds, the mammary cancer of 5% ~ 10% is familial.Suffer from breast cancer if any a close relative, then ill danger increases by 1.5 ~ 3 times; Suffer from breast cancer if any two close relatives, then morbidity is by increase by 7 times.The age of morbidity is lighter, and the danger suffered from breast cancer in relatives is larger, and mammary cancer has obvious Family inherited inclination.
Other: 1. corpus mamma densification 2. menarche early (<12 year), menopause late (>55 year) 3. unmarried, do not educate, late childbirth, non-lactation 4. suffer from benign breast disease do not treat in time 5. through hospital's biopsy confirm to suffer from atypical hyperplasia 6. chest accept too high dose radioactive rays irradiation 7. long-term taking exogenous estrogen 8. the fat 9. long-term excessive consumption of alcohol of post menopausal 10. carry the mutator gene relevant to mammary cancer (now known have BRCA-1, BRCA-2, p53, PTEN etc.).
2. diagnose
Britain NHS mammary cancer examination scheme is recommended: the crowd of age between 47 years old to 73 years old answers routine to carry out mammary gland x line photography examination.No matter sex, once mammary gland has abnormal situation, should as early as possible (normally fortnight) go local mammary gland training to go to a doctor, in order to avoid delay treatment, as required, generally must improve mammary gland x line, the inspection such as breast sonography and biopsy.Pathological examination is the gold standard of breast cancer diagnosis.
NHS (NationalHealthService), i.e. United Kingdom National medical service provider system, this individual system carries the important task ensureing Britain whole people socialized medicine health care always.
3. current treatment status
Because mammary cancer is a kind of hormone-dependent tumor, the regulation and control of multiple hormone in the growth receptors of cancer cells.Wherein, oestrogenic hormon plays vital effect in the developing of most of mammary cancer, and endocrine therapy is then by reducing body inner estrogen level or suppress estrogenic effect, reaching the growth of inhibition tumor cell.Which patient is applicable to making endocrine therapy, clinical is estrogen receptor (ER) by detecting patient breast cancer cell and progesterone receptor (PR), as all positive in both or arbitrary is positive, think at present, no matter age, menstruation situation, postoperatively all endocrine therapy should be accepted, as both are all negative, then postoperatively based on chemotherapy, Adjuvant Endocrine Therapy should do not recommended.For the infiltrative breast carcinoma patient of hormone receptor positive, HER-2 feminine gender, recommend Adjuvant Endocrine Therapy ± adjuvant chemotherapy, namely endocrine therapy should start after chemotherapy and radiation terminates, and can improve the lifetime of breast cancer patients on the one hand, can increase chemotherapy effect on the other hand.
Represent medicine 1. selective estrogen receptor modulators (oestrogenic hormon competitive inhibitor): tamoxifen (tamoxifen), this kind of medicine can suppress the effect of normal estradiol in body.The molecular structure of tamoxifen is similar to oestrogenic hormon, can be combined with the hormone receptor on breast cancer cell surface, thus stops the combination of normal estradiol and progestogen and acceptor in body.2. arimedex: fluon (letrozole sheet), Arimidex (anastrozole tablets), Exemestane, aromatizing enzyme produces the required a kind of organized enzyme of oestrogenic hormon process in women's body, suppress aromatizing enzyme effectively can reduce body inner estrogen level, play the effect of minimizing " key ", thus reduce its hormesis to cancer cells.3. castration medicine: Nuo Lei get (goserelin acetate sustained-release implant), Pre-menopausal Women body inner estrogen is primarily of ovarian secretion.We were by implementing oophorectomize (surgically and ray) to pre-menopausal women or adrenalectomizing and pituitectomy reduces estrogen level in the past.We can adopt medicine to reach similar effect now.4. hormone receptor modulator: fulvestrant, the major function of fulvestrant is the interaction destroying estrogen receptor and block between oestrogenic hormon and estrogen receptor, thus plays the effect of endocrine therapy.
Pabuk former times profit cloth (Palbociclib), chemistry 2-by name (pyridine-2-base is amino)-pyrido [2,3-d] pyrimidin-7-ones isethionate, structural formula is as follows:
The synthetic method of Pabuk former times profit cloth (Palbociclib) is a lot, and the method summary of related documents report is as follows:
(1) reported for work in patent WO20055426A1, WO200832157A2, US2005222163A1 prepare Pabuk former times profit cloth (Palbociclib) method as follows:
The method is Material synthesis fragment compound B and Compound C with compound 1, compound 2, compound 4, the method uses Pd/C (palladium charcoal) metal catalyst in preparation process, and synthesis step is long, and total recovery is low, production cost is higher, is not suitable for suitability for industrialized production.
Summary of the invention
Invention broadly provides the preparation method of profit cloth of a kind of isethionate Pabuk former times, whole synthetic technological condition is gentle, and aftertreatment is simple, and purity is high, and reaction cost is low.Its technical scheme is as follows:
Isethionate Pabuk former times profit cloth a preparation method, isethionate Pabuk former times profit cloth structural formula as shown in the formula shown in A, its synthetic route comprises the following steps:
(1) compound shown in compound and formula C shown in formula B is carried out substitution reaction and obtains compound shown in formula D:
(2) compound shown in formula D and vinyl-n-butyl ether Heck are reacted to obtain compound shown in formula E:
(3) by the compound shown in obtained formula F under methylsulphonic acid existence condition of compound shown in formula E:
(4) compound shown in formula F and hydroxyethylsulfonic acid salify are obtained compound shown in formula A.
Preferably, the reaction of step (1) is carried out under anaerobic, shielding gas be selected from nitrogen, argon gas and helium one or more; In step (1), reaction solvent is selected from one or more in toluene, DMF and tetrahydrofuran (THF); After having reacted, with cleaning solvent washing, described cleaning solvent be selected from ice methyl alcohol, ether, toluene, ethyl acetate, acetone and ethanol one or more.
Preferably, temperature of reaction in step (1) is 60-70 DEG C, reaction times is 7-9 hour, Grignard reagent is added when substitution reaction occurs step (1), described Grignard reagent is isopropylmagnesium chloride, the amount of substance of compound shown in isopropylmagnesium chloride with formula C is than being 1.5-2.0:1, and the 3-5 that the volume of described reaction solvent is compound by weight shown in formula C doubly.
Preferably, temperature of reaction in step (2) is 90-110 DEG C, reaction times is 3-5 hour, and the amount of substance of compound shown in vinyl-n-butyl ether with formula D is than being 3.0-4.0:1, and the 5-6 that the volume of described reaction solvent is compound by weight shown in formula D doubly; After having reacted, with cleaning solvent washing, described cleaning solvent be selected from ethyl acetate, propyl carbinol and ethanol one or more.
Preferably, temperature of reaction in step (3) is 50-60 DEG C, reaction times is 0.5-2 hour, described acid is 4.5-5.5:1 with the amount of substance ratio of compound shown in formula E, the 4.5-5.5 that the volume of described reaction solvent is compound by weight shown in formula E doubly, after having reacted, with cleaning solvent washing, described cleaning solvent be selected from ethanol, acetoneand ethyl acetate one or more.
Preferably, described acid is selected from one or more of hydrochloric acid, sulfuric acid, methylsulphonic acid and Glacial acetic acid.
Preferably, the reaction solvent in step (4) is selected from one or more of methyl alcohol, ethanol, Virahol and propyl carbinol.
Preferably, described hydroxyethylsulfonic acid is 3.0-4.0:1 with the amount of substance ratio of compound shown in formula F, the 5.0-6.0 that the volume of described reaction solvent is compound by weight shown in formula F doubly, after having reacted, with cleaning solvent washing, described cleaning solvent be selected from ethanol, propyl carbinol and ethyl acetate one or more.
Adopt aforesaid method to prepare isethionate Pabuk former times profit cloth, it has the following advantages:
Compared with the conventional method comparatively, method of the present invention has the advantage that synthesis yield is high, simple to operate, processing condition are gentle, finished product is stable.In addition, present invention effectively prevents use metal catalyst, simultaneously greatly reduce reactions steps, thus reduce reaction difficulty, and then simplify aftertreatment, improve yield and considerably reduce reaction cost, be beneficial to industrialized production.
Specific embodiment
Embodiment 1
A kind of preparation method of isethionate Pabuk former times profit cloth (Palbociclib), comprises the following steps:
(1) compound shown in compound and formula C shown in formula B is carried out substitution reaction and obtains compound shown in formula D:
810g (2.91mol) compd B, 3.0LTHF is dropped in 10L there-necked flask, vacuumized nitrogen 3 times, 20 DEG C of stirrings slowly dripped 1.2L isopropylmagnesium chloride (2.0MinTHF) after 30 minutes in system, 20 DEG C of insulated and stirred 1 hour, 770g (2.25mol) Compound C is dropped in system, vacuumized nitrogen 3 times, slowly in system, drip 1.2L isopropylmagnesium chloride (2.0MinTHF), after dropwising, be warming up to 60 DEG C of stirring reactions, TLC monitors reaction process.Reaction terminates to add 1.3L acetic acid and 1.3LTHF (tetrahydrofuran (THF)) mixed solution in backward reaction solution, has solid to separate out, suction filtration, filter cake is pulled an oar once with acetone, water, acetone respectively, 50 DEG C of forced air dryings, solid constant weight 1336g, faint yellow solid, yield 99.8%.
(2) compound shown in formula D and vinyl-n-butyl ether are carried out Heck and react to obtain compound shown in formula E:
Drop into 626.0g (1.07mol) Compound D, 3.6L propyl carbinol, 322.0g (3.22mol) ethene n-butyl ether, 332gDIPEA in 10L there-necked flask, nitrogen replacement 3 times, stirring at room temperature 30 minutes, adds 9.3gPd
2(dba)
3, nitrogen replacement 3 times, be warming up to 95 DEG C of stirring reactions after 3 hours, be cooled to 80 DEG C of insulated and stirred, TLC monitors reaction process.React completely in backward reaction solution and add 810mL water, 1.1L propyl carbinol, stir suction filtration after 30 minutes, in filtrate, add 380g1,2-propylene diamine, 1.2L water, be heated to 70 DEG C of stirring reactions 1 hour, heating is stopped to be cooled to stirred overnight at room temperature, suction filtration, filter cake propyl carbinol, water difference drip washing 2 times, 50 DEG C of forced air dryings, constant weight 410g, faint yellow solid, yield 64.5.1%.
(3) acidifying of compound shown in formula E is obtained compound shown in formula F:
Drop into 402g (0.67mol) compd E in 5L there-necked flask, 0.8L water, 1.5L acetone is warming up to 50-55 DEG C of stirring reaction 30 minutes, drip 305g (3.18mol) methylsulphonic acid+400mL water+400mL acetone mixture, system has a large amount of yellow solid to separate out instantaneously after slowly becoming clarification, controlling temperature of reaction 45-55 DEG C of system can be slowly entirely molten, and TLC monitors reaction process.Drip the 5%NaOH aqueous solution in the backward system of reaction ends, adjustment pH > 9, has a large amount of yellow solid to separate out, suction filtration, filter cake water and each drip washing of acetone once, 55 DEG C of forced air drying 8h, constant weight 295.0g, yield 95.6%.
(4) compound shown in formula F and hydroxyethylsulfonic acid salify are obtained compound shown in formula A:
In 5L there-necked flask, drop into 290.0g (0.65mol) free alkali, 1.2L methyl alcohol, stirring at room temperature, drip 75.2g isethionic acid (0.65mol) and 500mL methyl alcohol mixed liquor, system has a large amount of solid to separate out after becoming clarification gradually by suspension liquid instantaneously, continue stirring at room temperature 3 hours, suction filtration, filter cake methyl alcohol drip washing, 45 DEG C of forced air dryings, obtain faint yellow solid, constant weight 192.0g, yield 51.6%.
Relevant physico-chemical property, the spectroscopy data of Formula shown in formula A are as follows:
Fusing point: 200 DEG C; 1HNMR (300MHz, DMSOd6) δ (ppm): δ 10.41 (s, 0.75H), 9.03 (s, 0.25H), 8.98 (s, 2H), 8.12 (d, J=3.0Hz, 1H), 7.90 (d, J=9.1Hz, 1H), 7.63 (dd, J=9.1,3.0Hz, 1H), 5.84 (m, 1H), 3.40 (broad, 4H), 3.29 (broad, 4H), 2.43 (s, 3H), 2.33 (s, 3H), 2.21 (m, 2H), 1.91 (m, 2H), 1.79 (m, 2H), 1.59 (m, 2H);
MS (ES) m/z448.5 be [C31H33N5O4+H]+, mass-to-charge ratio 446.6 be [C2H6O3S-H]-, determine that the molecular weight of this product is 447.5 thus.
The instrument adopted in the various embodiments described above and reagent as follows:
X-4 type micro-meldometer; VarianMercuryplus-300MHz type nuclear magnetic resonance analyser, AGILENTLC-MSD-Trap-SL mass spectrograph.
Other reagent used is commercially available analytical pure or chemical pure, not purified before using.
Embodiment 2
(1) compound shown in compound and formula C shown in formula B is carried out substitution reaction and obtains compound shown in formula D:
810g (2.91mol) compd B, 3.9LTHF is dropped in 10L there-necked flask, vacuumized nitrogen 3 times, 20 DEG C of stirrings slowly dripped 1.2L isopropylmagnesium chloride (2.0MinTHF) after 30 minutes in system, 20 DEG C of insulated and stirred 1 hour, 770g (2.25mol) Compound C is dropped in system, vacuumized nitrogen 3 times, slowly in system, drip 1.2L isopropylmagnesium chloride (2.0MinTHF), after dropwising, be warming up to 70 DEG C of stirring reactions, TLC monitors reaction process.Reaction terminates to add 1.3L acetic acid and 1.3LTHF (tetrahydrofuran (THF)) mixed solution in backward reaction solution, has solid to separate out, suction filtration, filter cake is pulled an oar once with acetone, water, acetone respectively, 50 DEG C of forced air dryings, solid constant weight 1338g, faint yellow solid, yield 99.9%.
(2) compound shown in formula D and vinyl-n-butyl ether are carried out Heck and react to obtain compound shown in formula E:
Drop into 626.0g (1.07mol) Compound D, 3.8L propyl carbinol, 428.0g (4..28mol) ethene n-butyl ether, 332gDIPEA in 10L there-necked flask, nitrogen replacement 3 times, stirring at room temperature 30 minutes, adds 9.3gPd
2(dba)
3, nitrogen replacement 3 times, be warming up to 100 DEG C of stirring reactions after 3 hours, be cooled to 80 DEG C of insulated and stirred, TLC monitors reaction process.React completely in backward reaction solution and add 810mL water, 1.1L propyl carbinol, stir suction filtration after 30 minutes, in filtrate, add 380g1,2-propylene diamine, 1.2L water, be heated to 70 DEG C of stirring reactions 1 hour, heating is stopped to be cooled to stirred overnight at room temperature, suction filtration, filter cake propyl carbinol, water difference drip washing 2 times, 50 DEG C of forced air dryings, constant weight 416g, faint yellow solid, yield 65.5.1%.
(3) acidifying of compound shown in formula E is obtained compound shown in formula F:
Drop into 402g (0.67mol) compd E in 5L there-necked flask, 0.8L water, 1.8L acetone is warming up to 60 DEG C of stirring reactions 30 minutes, drip 360g (3.68mol) methylsulphonic acid+400mL water+400mL acetone mixture, system has a large amount of yellow solid to separate out instantaneously after slowly becoming clarification, controlling temperature of reaction 45-55 DEG C of system can be slowly entirely molten, and TLC monitors reaction process.Drip the 5%NaOH aqueous solution in the backward system of reaction ends, adjustment pH > 9, has a large amount of yellow solid to separate out, suction filtration, filter cake water and each drip washing of acetone once, 55 DEG C of forced air drying 8h, constant weight 298.0g, yield 96.2%.
(4) compound shown in formula F and hydroxyethylsulfonic acid salify are obtained compound shown in formula A:
In 5L there-necked flask, drop into 290.0g (0.65mol) free alkali, 1.2L methyl alcohol, stirring at room temperature, drip 98.2g isethionic acid (0.78mol) and 500mL methyl alcohol mixed liquor, system has a large amount of solid to separate out after becoming clarification gradually by suspension liquid instantaneously, continue stirring at room temperature 3 hours, suction filtration, filter cake methyl alcohol drip washing, 45 DEG C of forced air dryings, obtain faint yellow solid, constant weight 196.0g, yield 52.5%.
Known by the preparation method in embodiment 1 and embodiment 2, present method technique is simple, and processing condition are gentle, and aftertreatment is simple, and yield is high, and purity is high, and reaction cost is low, is easy to realize suitability for industrialized production.
To one skilled in the art, according to technical scheme described above and design, other various corresponding change and deformation can be made, and all these change and deformation all should belong within the protection domain of the claims in the present invention.
Claims (8)
1. isethionate Pabuk former times profit cloth a preparation method, it is characterized in that: isethionate Pabuk former times profit cloth structural formula as shown in the formula shown in (A), its synthetic route comprises the following steps:
(1) compound shown in compound formula (B) Suo Shi and formula (C) is carried out substitution reaction and obtains compound shown in formula (D):
(2) compound formula (D) Suo Shi and vinyl-n-butyl ether Heck are reacted to obtain the shown compound of formula (E):
(3) by the compound shown in obtained formula (F) under methylsulphonic acid existence condition of compound formula (E) Suo Shi:
(4) compound formula (F) Suo Shi and hydroxyethylsulfonic acid salify are obtained compound shown in formula (A).
2. isethionate Pabuk former times according to claim 1 profit cloth preparation method, it is characterized in that: the reaction of step (1) is carried out under anaerobic, shielding gas be selected from nitrogen, argon gas and helium one or more; In step (1), reaction solvent is selected from one or more in toluene, DMF and tetrahydrofuran (THF); After having reacted, with cleaning solvent washing, described cleaning solvent be selected from ice methyl alcohol, ether, toluene, ethyl acetate, acetone and ethanol one or more.
3. isethionate Pabuk former times according to claim 2 profit cloth preparation method, it is characterized in that: the temperature of reaction in step (1) is 60-70 DEG C, reaction times is 7-9 hour, Grignard reagent is added when substitution reaction occurs step (1), described Grignard reagent is isopropylmagnesium chloride, the amount of substance of compound shown in isopropylmagnesium chloride and formula (C) is than being 1.5-2.0:1, and the volume of described reaction solvent is 3-5 times of compound by weight shown in formula (C).
4. isethionate Pabuk former times according to claim 1 profit cloth preparation method, it is characterized in that: the temperature of reaction in step (2) is 90-110 DEG C, reaction times is 3-5 hour, the amount of substance of compound shown in vinyl-n-butyl ether and formula (D) is than being 3.0-4.0:1, and the volume of described reaction solvent is 5-6 times of compound by weight shown in formula (D); After having reacted, with cleaning solvent washing, described cleaning solvent be selected from ethyl acetate, propyl carbinol and ethanol one or more.
5. isethionate Pabuk former times according to claim 1 profit cloth preparation method, it is characterized in that: the temperature of reaction in step (3) is 50-60 DEG C, reaction times is 0.5-2 hour, the amount of substance of compound shown in described acid and formula (E) is than being 4.5-5.5:1, the volume of described reaction solvent is 4.5-5.5 times of compound by weight shown in formula (E), after having reacted, with cleaning solvent washing, described cleaning solvent be selected from ethanol, acetoneand ethyl acetate one or more.
6. isethionate Pabuk former times according to claim 5 profit cloth preparation method, it is characterized in that: described acid is selected from one or more of hydrochloric acid, sulfuric acid, methylsulphonic acid and Glacial acetic acid.
7. isethionate Pabuk former times according to claim 1 profit cloth preparation method, it is characterized in that: the reaction solvent in step (4) is selected from one or more of methyl alcohol, ethanol, Virahol and propyl carbinol.
8. isethionate Pabuk former times according to claim 7 profit cloth preparation method, it is characterized in that: the amount of substance of compound shown in described hydroxyethylsulfonic acid and formula (F) is than being 3.0-4.0:1, the volume of described reaction solvent is 5.0-6.0 times of compound by weight shown in formula (F), after having reacted, with cleaning solvent washing, described cleaning solvent be selected from ethanol, propyl carbinol and ethyl acetate one or more.
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| WO2023035667A1 (en) * | 2021-09-07 | 2023-03-16 | 山东铂源药业股份有限公司 | Low-cost preparation method for palbociclib |
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