CN102516225A - Synthesis of novel medicine intermediate (R)-3-phenyldicarboximidopiperidine hydrochloride - Google Patents
Synthesis of novel medicine intermediate (R)-3-phenyldicarboximidopiperidine hydrochloride Download PDFInfo
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- CN102516225A CN102516225A CN2011103675109A CN201110367510A CN102516225A CN 102516225 A CN102516225 A CN 102516225A CN 2011103675109 A CN2011103675109 A CN 2011103675109A CN 201110367510 A CN201110367510 A CN 201110367510A CN 102516225 A CN102516225 A CN 102516225A
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- phenyldicarboximidopiperidine
- hydrochloride
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- benzyl
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Abstract
The invention relates to a synthesis technique of a novel medicine key intermediate (R)-3-phenyldicarboximidopiperidine hydrochloride. The synthesis technique comprises the following steps: condensing (R)-N-benzyl-3-aminopiperidine alkane and phthalic anhydride under the action of acid; acidifying the product with hydrochloric acid to obtain the (R)-N-benzyl-3-phenyldicarboximidopiperidine hydrochloride; and directly carrying out conventional hydrogenation on the (R)-N-benzyl-3-phenyldicarboximidopiperidine hydrochloride to obtain the needed (R)-3-phenyldicarboximidopiperidine hydrochloride. The invention has the advantages of low raw material price, simple step unit processes, low facility request and high safety, and is suitable for industrialized mass production; and the after-treatment and purification are simple to operate.
Description
Technical field
The present invention relates to the synthesis technique of a kind of Medicine key intermediate (R)-3-NSC 308847 piperidine hydrochlorate.
Background technology
(R)-3-amino piperidine alkane is synthetic Li Laliting (Linagliptin) (formula
4) one of critical segment.Li Laliting is the medicine of the novel therapeutic mellitus of international medicine company giant's Boehringer Ingelheim exploitation, has been in the stage of examining at present.In vitro study finds that Li Laliting is much higher to other DPP to the selectivity ratios of enzyme dipeptidyl peptidase (DPP) IV; And in mouse and rat body, all observe these article to DPPIV imitate by force, persistent restraining effect, and be better than other DPPIV suppressor factor.The clinical study result shows, Li Laliting can raise glucagon-like peptide (GLP-1) concentration, reduce type ii diabetes patient's blood sugar concentration and significantly reduce diabetic subject's glycolated hemoglobin (Hb1Ac) level.Patent (WO2006048427) discloses the synthetic route of Boehringer Ingelheim exploitation, relate to utilization (
R)-3-NSC 308847 piperidines tartrate (formula
1) and bromo heterocycle (formula
2) condensation under alkaline condition.This route why adopt (
RThe tartrate of)-3-NSC 308847 piperidines is because this chipal compounds is through D-(-)-tartrate the 3-NSC 308847 piperidines of racemization to be rolled over the branch preparation.That this patent relates to is synthetic (
R)-3-NSC 308847 piperidines tartrate technology is owing to existing following defective to make suitability for industrialized production run into bottleneck: (1) the first step needs high pressure (100 normal atmosphere), is unfavorable for large-scale production; (2) the first step need be to use expensive platinum-rhodium catalyst; (3) the 3rd steps needed to split with D-(-)-tartrate, needed the half the 3-NSC 308847 piperidines of waste in the split process, thereby cause (
R)-3-NSC 308847 piperidines tartrate (formula
1) total recovery have only 29-30%.
In addition, (R)-3-amino piperidine alkane also is the new drug A Gelieting benzoate (formula of the treatment diabetes B of Japanese Takeda company's exploitation and approved listing at present
9) critical segment, the operational path (CN1926128) for preparing the A Gelieting benzoate at present relates generally to (R)-3-amino piperidine heptane hydrochloride salt (formula
6) direct and Chloropyrimide fragment (formula
5) condensation under alkaline condition, product A Gelieting (formula then
7) directly become benzoate.Though this route can be accomplished the preparation of A Gelieting benzoate, condensation one step because (R)-3 amino of 3-amino piperidine alkane not protection be easy to generate impurity (formula
8).
Summary of the invention
Technical problem to be solved by this invention be to design a general preparation that cost is low, technology is easy (
R)-3-NSC 308847 piperidine hydrochlorate (formula
12) method, can conveniently realize the preparation of Li Laliting and A Gelieting benzoate from this midbody, avoid synthetic at present Li Laliting and A Gelieting benzoate defective workmanship.
Synthetic route of the present invention is following:
Starting raw material (
R)-1-benzyl-3-amino piperidine alkane (formula
10) having realized commercialization at present, I the CN 101955457A of house journal has carried out patent protection to its operational path, and at present industrial scale has reached tonne.This raw material and Tetra hydro Phthalic anhydride carry out condensation under the acid effect, obtain behind the product hcl acidifying (
R)-N-benzyl-3-NSC 308847 piperidine hydrochlorate (formula
11), that the direct conventional hydrogenation of the latter promptly gets is required (
R)-3-NSC 308847 piperidine hydrochlorate (formula
12).
The employed solvent of this route the first step comprises one or more in toluene, benzene, the YLENE; Employed acid comprises one or more in Glacial acetic acid min. 99.5, propionic acid and the formic acid; Temperature of reaction is that room temperature is to refluxing.
This second step of route catalyzer comprises Pd/C, PtO
2, Pt/C, Ranney Ni; Employed solvent comprises one or more the mixed solvent in methyl alcohol, ethanol, propyl alcohol, the ETHYLE ACETATE; The pressure of hydrogen is the 2-40 normal atmosphere.
The present invention make (
R)-3-NSC 308847 piperidine hydrochlorate (formula
12) the structure warp
1H-NMR confirms that purity is high, and the technology favorable reproducibility.
Method of the present invention also has the following advantages:
1, the prices of raw and semifnished materials in each step are lower, on market, all can purchase in a large number, thereby reduce cost; And starting raw material all is my company's fixed product (protection of synthesis technique patent applied for), can tonne production.
2, each step unit operation is simple, and equipment requirements is low, and is safe, and aftertreatment and purification process are simple, is fit to industrialized production.
3, through the preparation of this operational path (
R)-3-NSC 308847 piperidine hydrochlorate (formula
12), can realize the synthetic of Li Laliting and A Gelieting benzoate easily.Midbody (formula
12) and Chloropyrimide (formula
5) reaction obtains midbody (formula
13), the latter removes phthalic imidine protection base and obtains A Geliting (formula
7), last alcohol adds the preparation that the phenylformic acid salify is accomplished the A Geliting benzoate for solvent.(
R)-3-NSC 308847 piperidine hydrochlorate (formula
12) and heterocycle fragment (formula
2) under the alkali effect reaction obtain compound (formula
3), the latter removes the preparation that phthalic imidine protection base is accomplished Li Laliting under the alkali condition.Operational path is following:
Embodiment
Can understand the present invention more specifically through following embodiment, but it is to illustrate rather than limit scope of the present invention.
Embodiment 1Preparation (
R)-N-benzyl-3-NSC 308847 piperidine hydrochlorate (formula
11)
Compound
10(5.0g), Glacial acetic acid min. 99.5 (20mL), toluene (10mL), Tetra hydro Phthalic anhydride (3.87g) join in the reaction flask successively, system temperature rising reflux 1h, air distillation 2h, (TLC tracks to raw material to steam a little acetic acid
10Disappear), system is cooled to less than 60 ℃, and underpressure distillation is to there not being cut.Resistates adds ETHYLE ACETATE and deionized water, and stirring and dissolving is complete, and concentrated hydrochloric acid is regulated pH=1 ~ 3, stirring at normal temperature, and a large amount of solids are separated out.Behind the solid suction filtration, the decompression oven drying obtains compound
11(8.05g).Yield 84.0%, purity>95%.
Embodiment 2Preparation (
R)-N-benzyl-3-NSC 308847 piperidine hydrochlorate (formula
11)
Compound
10(10.0g), Glacial acetic acid min. 99.5, toluene and Tetra hydro Phthalic anhydride (7.8g) join in the reaction flask successively, system temperature rising reflux 1h, underpressure distillation is to there not being cut.Resistates adds ETHYLE ACETATE and deionized water, and stirring and dissolving is complete, and concentrated hydrochloric acid is regulated pH=1 ~ 3, and stirring at normal temperature 20-30 minute, a large amount of solids were separated out.The solid suction filtration, the decompression oven drying obtains compound
11(15.6g), yield 83.0%, Chun Du>97%.
Embodiment 3Preparation (
R)-3-NSC 308847 piperidine hydrochlorate (formula
12)
Compound
11(12.0g) be dissolved in the ethanol, add 7.5% Pd/C (1.0g).System is warming up to 70
oC, hydrogenation 20h under 10 normal atmosphere.System adds methyl alcohol and stirs, and suction filtration is removed Pd/C, and filtrate decompression is removed the back gained solid that desolvates and added washing with alcohol.50 ℃-100 of solids
oThe C oven dry obtains product
12(6.69g), purity 98.1%, yield 74.6%.
1H?NMR?(300?MHz):?δ?7.61?(m,?4H),?4.35-4.28?(m,?1H),?3.52?(t,?
J?=?11.1?Hz,?1H),?3.32-3.24?(m,?2H),?2.91?(t,?
J?=?9.6?Hz,?1H),?2.21-2.08?(m,?1H),?1.95-1.62?(m,?3H).
Embodiment 4Preparation (
R)-3-NSC 308847 piperidine hydrochlorate (formula
12)
Compound
11(5.0g) be dissolved in the ethanol, add 7.5% Pd/C (0.5g).System is warming up to 70
oC, hydrogenation 5h under 15 normal atmosphere.System adds methyl alcohol and stirs, and suction filtration is removed Pd/C, and filtrate decompression is removed the back gained solid (weight in wet base 4.1g, purity 98.3%) that desolvates and added an amount of washing with alcohol.50 ℃-100 of solids
oThe C oven dry obtains product
12(2.81g), purity 99%, yield 75.1%.
Claims (8)
1. one kind prepares (R)-3-NSC 308847 piperidine hydrochlorate (formula
12) process method, its technical characterictic is that this method comprises following reaction:
。
2. the method for claim 1 is characterized in that this reacts employed starting raw material and is (R)-1-benzyl-3-amino piperidine alkane (formula
10) and Tetra hydro Phthalic anhydride.
3. the method for claim 1 is characterized in that the employed solvent of its first step comprises one or more in toluene, benzene, the YLENE.
4. the method for claim 1 is characterized in that the employed acid of its first step comprises one or more of Glacial acetic acid min. 99.5, propionic acid and formic acid.
5. the method for claim 1 is characterized in that its first step temperature of reaction is that room temperature is to refluxing.
6. the method for claim 1 is characterized in that its employed catalyzer of second step comprises Pd/C, PtO
2, among the Pt/C, Ranney Ni one or more.
7. the method for claim 1 is characterized in that its employed solvent of second step comprises one or more the mixed solvent in methyl alcohol, ethanol, propyl alcohol, the ETHYLE ACETATE.
8. the method for claim 1 is characterized in that its employed hydrogen pressure of second step is the 2-40 normal atmosphere.
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| CN2011103675109A CN102516225A (en) | 2011-11-18 | 2011-11-18 | Synthesis of novel medicine intermediate (R)-3-phenyldicarboximidopiperidine hydrochloride |
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|---|---|---|---|
| CN2011103675109A CN102516225A (en) | 2011-11-18 | 2011-11-18 | Synthesis of novel medicine intermediate (R)-3-phenyldicarboximidopiperidine hydrochloride |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101048409A (en) * | 2004-11-05 | 2007-10-03 | 贝林格尔·英格海姆国际有限公司 | Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines |
-
2011
- 2011-11-18 CN CN2011103675109A patent/CN102516225A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101048409A (en) * | 2004-11-05 | 2007-10-03 | 贝林格尔·英格海姆国际有限公司 | Method for producing chiral 8-(3-amino-piperidin-1-yl)-xanthines |
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Application publication date: 20120627 |