CN109575021B - Preparation method of thuja occidentalis - Google Patents
Preparation method of thuja occidentalis Download PDFInfo
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- CN109575021B CN109575021B CN201910060686.6A CN201910060686A CN109575021B CN 109575021 B CN109575021 B CN 109575021B CN 201910060686 A CN201910060686 A CN 201910060686A CN 109575021 B CN109575021 B CN 109575021B
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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
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
A preparation method of piperazicil relates to the field of organic synthesis, and the piperazicil is obtained by taking a compound I as a starting raw material and carrying out five-step reaction. The method has the advantages of simple operation, low requirement on equipment, easily obtained raw materials, mild reaction conditions, high yield and suitability for industrial production.
Description
Technical Field
The invention relates to the field of organic synthesis, and particularly relates to a preparation method of pimari cypress cilaride.
Background
Piperazine is a targeted CDK4/6 inhibitor, first reported in U.S. Pat. No. 6936612. The piperazili selectively inhibits cyclin dependent kinases 4 and 6(CDK4/6), restores cell cycle control, and blocks tumor cell proliferation. Pipariciclib in combination with letrozole for initial endocrine basic treatment of postmenopausal female estrogen receptor positive (ER +), human epidermal growth factor receptor 2 negative (HER2-) advanced or metastatic breast cancer that has not previously received systemic treatment to control advanced disease; fulvestrant in combination is used in hormone receptor positive (HR +), HER 2-advanced or metastatic breast cancer patients with disease progression after endocrine treatment.
In the prior art, various synthesis methods for the piperazicil exist, but more or less problems of great difficulty in obtaining raw materials, great toxicity of reaction reagents, high price, poor reaction reproducibility, low reaction yield and the like exist.
Disclosure of Invention
The invention aims to provide a preparation method of thujaplicin, which has the advantages of simple operation, low requirement on equipment, easily obtained raw materials, mild reaction conditions, high yield and suitability for industrial production.
The embodiment of the invention is realized by the following steps:
a method of preparing thujaplici, comprising:
reacting the compound I with malonic diester to obtain a compound II;
closing the ring of the compound II under the action of an alkali reagent to obtain a compound III;
carrying out substitution reaction on the compound III and the compound IV to obtain a compound V;
reacting the compound V with a methylating agent to obtain a compound VI;
deprotecting the compound VI to obtain piparixiline;
wherein the structural formula of the compound I is
The structural formula of the compound II is
The structural formula of the compound III is
The structural formula of the compound IV is
The structural formula of the compound V isThe structural formula of the compound VI is
The structural formula of the piperacillin is shown as
Wherein R is C1-C4 alkyl, and PG is an amino protecting group.
The embodiment of the invention has the beneficial effects that:
the embodiment of the invention provides a preparation method of thujaplicin, which takes a compound I as a starting material and obtains the thujaplicin through five-step reaction. The method has the advantages of simple operation, low requirement on equipment, easily obtained raw materials, mild reaction conditions, high yield and suitability for industrial production.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The following is a detailed description of the method for preparing thujaplicin according to the embodiment of the present invention.
The embodiment of the invention provides a preparation method of thujaplicin, which comprises the following steps:
s1, reacting a compound I with malonic diester to obtain a compound II.
Wherein the structural formula of the compound I is
The structural formula of the compound II is
Wherein R is C1-C4 alkyl, including but not limited to methyl, ethyl, n-propyl, isopropyl, tert-butyl, etc. Correspondingly, the malonic diester can be dimethyl malonate, diethyl malonate, diisopropyl malonate, di-tert-butyl malonate, and the like.
Further, the molar ratio of compound I to malonic diester is 1: 1.8 to 2.2. Within the above ratio range, the malonic acid diester, which is relatively inexpensive and easily available, can be in excess, thereby ensuring complete reaction of the compound I and improving the reaction yield.
Further, the reaction of the compound I and malonic diester is carried out at-10-0 ℃ under the catalysis of organic base by using Lewis acid as an activating reagent. The compound I and the malonic diester are actually nucleophilic attack of alpha-C of the malonic diester to carbonyl of the compound I, the Lewis acid can be combined with the carbonyl to activate the carbonyl and increase electrophilicity of carbonyl carbon, and the organic base can promote the alpha-C to pull hydrogen and increase the nucleophilicity of the alpha-C, so that the aim of improving the yield is fulfilled. Preferably, the lewis acid comprises at least one of aluminum chloride, titanium chloride, zinc chloride, and tin chloride; preferably, the organic base comprises at least one of triethylamine, pyridine, piperidine and DBU. More preferably, the molar ratio of compound I to lewis acid is 1: 4 to 6. The molar ratio of compound I to organic base is 1: 4 to 6.
The preparation method of the thujaplicin provided by the embodiment of the invention further comprises the following steps:
s2, closing the ring of the compound II under the action of an alkali reagent to obtain a compound III.
Wherein the structural formula of the compound III is
Wherein R is C1-C4 alkyl.
Furthermore, the ring closing reaction of the compound II is realized by nucleophilic attack of ester group in amino molecule, and an alkali reagent can assist in hydrogen extraction, so that the reaction yield is improved. Preferably, the base reagent comprises at least one of potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, KHMDS, LiHMDS, and LDA.
Further, the molar ratio of compound II to the basic agent is 1: 0.05 to 0.2. Within the above ratio range, the compound II has high ring-closing efficiency and fewer side reactions, which is favorable for obtaining high yield.
The preparation method of the thujaplicin provided by the embodiment of the invention further comprises the following steps:
and S3, carrying out substitution reaction on the compound III and the compound IV to obtain a compound V.
Wherein the structural formula of the compound IV is
The structural formula of the compound V is
Wherein R is C1-C4 alkyl, and PG is an amino protecting group.
Preferably, PG comprises any one of Cbz, Boc, Fmoc, PMB, Bn. More preferably, PG is Boc.
Further, the molar ratio of compound III to compound IV is 1: 1 to 1.2. The reaction of the compound III and the compound IV is carried out at-10 to 0 ℃ in the presence of an alkali reagent. Under the above reaction conditions, the compound III can be reacted sufficiently to obtain the compound V in a high yield. Preferably, the molar ratio of compound III to the basic agent is 1: 1.5 to 3.
The preparation method of the thujaplicin provided by the embodiment of the invention further comprises the following steps:
and S4, reacting the compound V with a methylation reagent to obtain a compound VI.
Wherein the structural formula of the compound VI is
In the formula, PG is an amino protecting group.
Further, the molar ratio of compound V to methylating agent is 1: 2 to 5. Within the above ratio range, the compound V can be reacted sufficiently to obtain the compound VI in a high yield. Preferably, the methylating agent comprises at least one of methyllithium, methylmagnesium bromide and dimethylzinc. More preferably, the methylating agent is methyllithium.
The preparation method of the thujaplicin provided by the embodiment of the invention further comprises the following steps:
and S5, deprotecting the compound VI to obtain the piperazicilli.
Wherein the structural formula of the piperacillin is shown in the specification
The deprotection conditions for compound VI vary depending on PG. When Boc is used as PG, deprotection of compound VI is carried out by reacting compound VI with hydrochloric acid to give the hydrochloride salt of pipbicide. The reaction is carried out at room temperature by stirring, the reaction is faster, the yield is higher, and the excessive hydrochloric acid is easy to remove, so that the product is easier to purify.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
This example provides a process for the preparation of compound II having the chemical reaction formula
The preparation method comprises the following specific steps:
s1, adding 12mL of THF into a 100mL three-necked bottle, and reducingHeating to-10-0 ℃, and dripping TiCl4A solution of dichloromethane (12g/12g) is added dropwise to a solution of 3.8g (15.9mmol) of Compound I in THF as a mixture with 5.08g (31.7mmol) of diethyl malonate.
S2, after the dropwise addition is finished, stirring for 5min, dropwise adding 6.3g of pyridine, and reacting at room temperature overnight.
And S3, detecting the reaction by TLC. Water dilution was added, extraction was performed with ethyl acetate, the organic phase was concentrated to dryness, and the concentrate was purified by column chromatography to give Compound II (5.6g, yield 93%).
Compound II was characterized as follows:
1H-NMR(400MHz，DMSO):1.37(s,6H),1.61～1.68(m,4H),1.81～1.89(m,4H),2.43(s,3H),2.45(s,1H),4.21～4.37(m,4H),7.65(s,1H),9.16(s,1H).
example 2
This example provides a process for the preparation of compound III having the chemical reaction formula
The preparation method comprises the following specific steps:
s1, 38.1g (0.1mol) of the compound II is dissolved in 300mL of THF, and a 1.1g (0.01mol) potassium tert-butoxide/10 mL of THF solution is added dropwise thereto at room temperature, followed by stirring at room temperature for 5 minutes.
And S2.TLC detection, and column chromatography purification to obtain the compound III (32.1g, yield 95.8%).
Example 3
This example provides a process for the preparation of Compound V, having the chemical reaction formula
The preparation method comprises the following specific steps:
s1, adding 20mL of toluene, 2g of compound III and 1.7g of compound IV into a 100mL reaction bottle, cooling to-10-0 ℃, dropwise adding 1.8g of lithium hexamethyldisilazide (LiHMDS), and reacting for half an hour after dropwise adding.
S2.TLC detection reaction is finished, ammonium chloride aqueous solution is added for quenching, ethyl acetate extraction is carried out, drying and concentration are carried out, and column chromatography purification is carried out to obtain the compound V (3g, yield 88.2%).
Example 4
This example provides a process for the preparation of Compound VI having the chemical reaction formula
The preparation method comprises the following specific steps:
s1, adding 50mL of THF and 5g of compound V into a reaction bottle, cooling to 0-10 ℃, dropwise adding 16mL of 1.6M methyllithium ethyl ether solution, and stirring to react for 1 hour after dropwise adding.
S2, adding an ammonium chloride aqueous solution to quench the reaction, adding ethyl acetate to extract, drying the organic phase sodium sulfate, concentrating, and carrying out column chromatography to obtain a compound VI (4.2g, yield 89.4%).
Example 5
This example provides a process for the preparation of a thujaplicin according to the chemical reaction formula
The preparation method comprises the following specific steps:
s1. Add 2g of Compound VI to the reaction flask, and 10mL of 98% hydrogen chloride in ethyl acetate and stir at room temperature for 1 hour.
S2, filtering, and draining a filter cake to obtain the hydrochloride of the pipabride (white solid, 1.7g, yield 96%).
The method of the embodiment 1-5 is adopted to synthesize the piparix bescenri, the total reaction yield of each step is more than 85%, the total yield reaches more than 65%, and the synthesis efficiency is high. In addition, the raw materials for each step of reaction are easy to obtain, the operation is simple, the reaction conditions are mild, and the method is suitable for large-scale industrial production and has high application value.
In summary, the embodiments of the present invention provide a method for preparing pimavalia cheirica, which uses compound I as a starting material to obtain the pimavalia cheirica through five-step reaction. The method has the advantages of simple operation, low requirement on equipment, easily obtained raw materials, mild reaction conditions, high yield and suitability for industrial production.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (12)
1. A preparation method of thujaplicin is characterized by comprising the following steps:
reacting the compound I with malonic diester to obtain a compound II;
closing the ring of the compound II under the action of an alkali reagent to obtain a compound III;
carrying out substitution reaction on the compound III and a compound IV to obtain a compound V;
reacting the compound V with a methylating agent to obtain a compound VI;
deprotecting the compound VI to obtain the piparixiline;
wherein the structural formula of the compound I is
The structural formula of the compound II is
The structural formula of the compound III is
The structural formula of the compound IV is
The structural formula of the compound V is
The structural formula of the compound VI is
The structural formula of the piperacillin is shown as
；
In the formula, R is C1-C4 alkyl, and PG is an amino protecting group; and the molar ratio of compound II to the base reagent is 1: 0.05 to 0.2; the reaction of the compound I and the malonic diester is carried out under the catalysis of organic base by taking Lewis acid as an activating reagent.
2. The method of claim 1, wherein PG comprises any one of Cbz, Boc, Fmoc, PMB, Bn.
3. The method according to claim 1, wherein the molar ratio of compound I to malonic diester is 1: 1.8 to 2.2.
4. The preparation method according to claim 3, wherein the reaction of the compound I and the malonic acid diester is carried out at-10 to 0 ℃ under the catalysis of an organic base and with Lewis acid as an activating agent.
5. The production method according to claim 4, wherein the Lewis acid includes at least one of aluminum chloride, titanium chloride, zinc chloride, and tin chloride.
6. The method according to claim 4, wherein the organic base comprises at least one of triethylamine, pyridine, piperidine, and DBU.
7. The method of claim 1, wherein the base reagent comprises at least one of potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, KHMDS, LiHMDS and LDA.
8. The method according to claim 7, wherein the molar ratio of the compound III to the compound IV is 1: 1 to 1.2.
9. The preparation method according to claim 8, wherein the reaction of the compound III with the compound IV is carried out at-10 to 0 ℃ in the presence of the alkali reagent.
10. The method of claim 1, wherein the molar ratio of compound V to methylating agent is 1: 2 to 5.
11. The method of claim 8, wherein the methylating agent comprises at least one of methyllithium, methylmagnesium bromide and dimethylzinc.
12. A process for the preparation of the hydrochloride salt of pipabriside according to claim 1, wherein PG is Boc and deprotection of compound VI is carried out by reacting compound VI with hydrochloric acid to give the hydrochloride salt of pipabriside.
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| CN105153149A (en) * | 2015-07-29 | 2015-12-16 | 江苏中邦制药有限公司 | Preparation method for selective kinases inhibitor Palbociclib |
| CN106220627A (en) * | 2016-07-31 | 2016-12-14 | 合肥远志医药科技开发有限公司 | A kind of industrialized process for preparing of high-purity Pabuk former times profit cloth |
| WO2017072543A1 (en) * | 2015-10-28 | 2017-05-04 | Egis Gyógyszergyár Zrt. | Palbociclib salts |
| CN106632313A (en) * | 2016-03-04 | 2017-05-10 | 上海贤鼎生物科技有限公司 | Novel important intermediate for anticancer drug palbociclib and compounding process |
| US20180207100A1 (en) * | 2015-06-04 | 2018-07-26 | Pfizer Inc. | Solid dosage forms of palbociclib |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180207100A1 (en) * | 2015-06-04 | 2018-07-26 | Pfizer Inc. | Solid dosage forms of palbociclib |
| CN105153149A (en) * | 2015-07-29 | 2015-12-16 | 江苏中邦制药有限公司 | Preparation method for selective kinases inhibitor Palbociclib |
| WO2017072543A1 (en) * | 2015-10-28 | 2017-05-04 | Egis Gyógyszergyár Zrt. | Palbociclib salts |
| CN106632313A (en) * | 2016-03-04 | 2017-05-10 | 上海贤鼎生物科技有限公司 | Novel important intermediate for anticancer drug palbociclib and compounding process |
| CN106220627A (en) * | 2016-07-31 | 2016-12-14 | 合肥远志医药科技开发有限公司 | A kind of industrialized process for preparing of high-purity Pabuk former times profit cloth |
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