CN107652291A - A kind of method for preparing chiral tetrahydropyran derivatives - Google Patents
A kind of method for preparing chiral tetrahydropyran derivatives Download PDFInfo
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- CN107652291A CN107652291A CN201610594375.4A CN201610594375A CN107652291A CN 107652291 A CN107652291 A CN 107652291A CN 201610594375 A CN201610594375 A CN 201610594375A CN 107652291 A CN107652291 A CN 107652291A
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- solvent
- compound
- preparing chiral
- ether
- tetrahydropyran derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
The invention discloses a kind of preparation method of chiral tetrahydropyran derivatives, it is from compound 1 and compound 3s, or from compound 2 and compound 3s, it is only necessary to one pot reaction, you can obtain compound 5, method is simple, and reaction is fast, without separating intermediate product.
Description
Technical field
The invention belongs to the field of chemical synthesis, and in particular to a kind of method for preparing chiral tetrahydropyran derivatives 5.Chemical combination
Thing 5 is a kind of DPPIV inhibitor.
Background technology
Existing more documents【1)Arroyo,I.；Krueger,D.；Chen,P.；Moment,A.；Biftu,T.；Sheen,
F.；Zhang,Y.WO2013003249A1.2)Biftu,T.；Chen,P.；Cox,J.M.；Weber,
A.E.US20100120863A1.3)Biftu,T.；Sinha-Roy,R.；Chen,P.；Qian,X.；Feng,D.；Kuethe,
J.T.；Scapin,G.；Gao,Y.D.；Yan,Y.；Krueger,D.；Bak,A.；Eiermann,G.；He,J.；Cox,J.；
Hicks,J.；Lyons,K.；He,H.；Salituro,G.；Tong,S.；Patel,S.；Doss,G.；Petrov,A.；Wu,J.；
Xu,S.S.；Sewall,C.；Zhang,X.；Zhang,B.；Thornberry,N.A.；Weber,
A.E.J.Med.Chem.2014,57,3205-3212.4)Zacuto,M.J.；Dunn,R.F.；Moment,A.J.；Janey,
J.M.；Lieberman,D.；Sheen,F.；Bremeyer,N.；Scott,J.；Kuethe,J.T.；Tan,L.；Chen,
Q.WO2013003250A1.5)Chung,J.Y.L.；Scott,J.P.；Anderson,C.；Bishop,B.；Bremeyer,N.；
Cao,Y.；Chen,Q.；Dunn,R.；Kassim,A.；Lieberman,D.；Moment,A.J.；Sheen,F.；Zacuto,
M.Org.Process Res.Dev.2015,19,1760–1768.】Describe the synthetic method of compound 5.It the following is several generations
The method of table, benzene sulfonate 2 is obtained after removing Boc protections by compound 1, then carry out reduction amination with chipal compounds 3 and obtain
To compound 4, finally take off Boc and protect to obtain 5.Or by compound 1 remove Boc protection after, in one pot with chipal compounds
3 progress reduction aminations obtain compound 4, finally take off Boc and protect to obtain 5.
Because the compound 7 generated after the directly de- Boc of chipal compounds 3 is very unstable, so known production line is necessary
First pass through reduction amination and obtain compound 4, then de- Boc protects to obtain compound 5.
The content of the invention
The defects of to overcome in the prior art, new chiral tetrahydropyran derivatives 5 are prepared the invention provides a kind of
Method, it comprises the following steps：
The first step：De- Boc protections reaction is carried out after compound 1 and compound 3 are mixed, obtains compound 6 and compound 7
Stable mixed solution；
Second step：With reducing agent reductive amination process is occurred into for the stable mixed solution in one pot, directly obtains production
Thing 5.
Wherein,
The de- Boc protection reactions of the first step are preferably carried out in the presence of solvent, and the solvent is trifluoroacetic acid or trifluoro second
The mixture of acid and another one or more solvent, " another one or more solvent " is selected from：Ether solvent, such as second
Ether, t-butyl methyl ether, isopropyl ether, 2- methyltetrahydrofurans, tetrahydrofuran etc.；Aromatic solvent, such as toluene, benzene etc.；Alkane
Solvent, for example, n-hexane, hexamethylene etc.；Halogenated hydrocarbon solvent, such as dichloromethane, symmetrical dichloroethanes, asymmetric dichloroethanes
Deng；Amide solvent, such as formamide, DMF, DMA, 1-METHYLPYRROLIDONE etc..
The temperature of Boc protection reactions is taken off described in the first step between -40 degrees Celsius to+50 degrees Celsius, is preferably -10 Celsius
Spend between+25 degrees Celsius, more preferably between 0 degree Celsius to 5 degrees Celsius.
The time of Boc protection reactions is taken off described in the first step between 1 hour to 24 hours.
Reacted by the first step, after obtaining the stable mixed solution of compound 6 and compound 7, it is not necessary to remove the first step
The solvent of reaction, particularly trifluoroacetic acid solvent, you can carry out the reductive amination process described in second step.
Reductive amination process described in second step is carried out preferably in the presence of amide solvent, and the amide solvent is N, N-
One in dimethyl acetamide, N,N-dimethylformamide, N- methylacetamides, 1-METHYLPYRROLIDONE and formamide etc.
Kind is several, and the amide solvent is preferably dimethyl acetamide.
In reductive amination process described in second step, the reducing agent is sodium triacetoxy borohydride or cyano group hydroboration
Sodium.
Reductive amination process described in second step is carried out preferably in the presence of alkaloid, and the alkaloid is selected from three
One in ethamine, diisopropyl ethyl amine, trimethylamine, piperidines, piperazine, pyridine, morpholine, crassitude and pyrrolidines etc.
Kind is a variety of.
The temperature of reductive amination process described in second step is preferably -10 Celsius between -40 degrees Celsius to+50 degrees Celsius
Spend between+25 degrees Celsius, more preferably between 0 degree Celsius to 5 degrees Celsius.
The time of reductive amination process described in second step is between 1 hour to 24 hours.
Similar, present invention also offers the method that another kind prepares chiral tetrahydropyran derivatives 5, and it includes following step
Suddenly：
The first step：De- Boc protections reaction is carried out after compound 2 and compound 3 are mixed, obtains compound 6 and compound 7
Stable mixed solution；
Second step：With reducing agent reductive amination process is occurred into for the stable mixed solution in one pot, directly obtains production
Thing 5.
Wherein,
The de- Boc protection reactions of the first step are preferably carried out in the presence of solvent, and the solvent is trifluoroacetic acid or trifluoro second
The mixture of acid and another one or more solvent, " another one or more solvent " is selected from：Ether solvent, such as second
Ether, t-butyl methyl ether, isopropyl ether, 2- methyltetrahydrofurans, tetrahydrofuran etc.；Aromatic solvent, such as toluene, benzene etc.；Alkane
Solvent, for example, n-hexane, hexamethylene etc.；Halogenated hydrocarbon solvent, such as dichloromethane, symmetrical dichloroethanes, asymmetric dichloroethanes
Deng；Amide solvent, such as formamide, DMF, DMA, 1-METHYLPYRROLIDONE etc..
The temperature of Boc protection reactions is taken off described in the first step between -40 degrees Celsius to+50 degrees Celsius, is preferably -10 Celsius
Spend between+25 degrees Celsius, more preferably between 0 degree Celsius to 5 degrees Celsius.
The time of Boc protection reactions is taken off described in the first step between 1 hour to 24 hours.
Reacted by the first step, after obtaining the stable mixed solution of compound 6 and compound 7, it is not necessary to remove the first step
The solvent of reaction, particularly trifluoroacetic acid solvent, you can carry out the reductive amination process described in second step.
Reductive amination process described in second step is carried out preferably in the presence of amide solvent, and the amide solvent is N, N-
One in dimethyl acetamide, N,N-dimethylformamide, N- methylacetamides, 1-METHYLPYRROLIDONE and formamide etc.
Kind is several, and the amide solvent is preferably dimethyl acetamide.
In reductive amination process described in second step, the reducing agent is sodium triacetoxy borohydride or cyano group hydroboration
Sodium.
Reductive amination process described in second step is carried out preferably in the presence of alkaloid, and the alkaloid is selected from three
One in ethamine, diisopropyl ethyl amine, trimethylamine, piperidines, piperazine, pyridine, morpholine, crassitude and pyrrolidines etc.
Kind is a variety of.
The temperature of reductive amination process described in second step is preferably -10 Celsius between -40 degrees Celsius to+50 degrees Celsius
Spend between+25 degrees Celsius, more preferably between 0 degree Celsius to 5 degrees Celsius.
The time of reductive amination process described in second step is between 1 hour to 24 hours.
Beneficial effects of the present invention
By method made above, from compound 1 and compound 3s, or from compound 2 and compound 3s, it is only necessary to
One pot reaction, you can obtain compound 5, method is simple, and reaction is fast, without separating intermediate product.
Embodiment
The preparation of the compound of embodiment 1. (5)
The first step is reacted：
Trifluoroacetic acid (2.6mL, 35.0mmol) is cooled to 0 DEG C, adds compound 3 (598mg, 1.83mmol), chemical combination
Thing 1 (500mg, 1.74mmol), 0~2 DEG C of reaction 1h.
Second step reacts：
Into above-mentioned reaction solution, DMA (7.1mL, 76.3mmol) is slowly added to, triethylamine (2.4mL,
17.3mmol), temperature is no more than 15 DEG C in control；Reaction solution is cooled to 0 DEG C again, adds sodium triacetoxy borohydride
(516.3mg, 2.43mmol), 0~2 DEG C of reaction 5h；PH to 9, filtering finally are adjusted with ammoniacal liquor, filtrate adds water (60mL), uses acetic acid
Ethyl ester extracts 3 times (30mL x 3), merges organic phase, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent, by residue silicagel column
Isolate and purify (dichloromethane：Methanol (volume ratio)=20:1) product 5 (white solid, 436mg, 1.1mmol, yield, are obtained：
63%).Analyze data is consistent with document (J.Med.Chem.2014,57,3205-3212).
The preparation of the compound of embodiment 2. (5)
The first step is reacted：
Trifluoroacetic acid (0.45mL, 6.1mmol) is cooled to 0 DEG C, adds compound 3 (100mg, 0.30mmol), chemical combination
Thing 2 (111mg, 0.32mmol), 0~2 DEG C of reaction 1h.
Second step reacts：
Into above-mentioned reaction solution, DMA (1.3mL, 14.0mmol), triethylamine are slowly added to
(0.42mL, 3.0mmol), temperature is no more than 15 DEG C in control；Reaction solution is cooled to 0 DEG C again, adds triacetoxy boron hydride
Sodium (90.6mg, 0.43mmol), 0~2 DEG C of reaction 5h；PH to 9, filtering finally are adjusted with ammoniacal liquor, filtrate adds water (15mL), uses acetic acid
Ethyl ester extracts 3 times (10mL x 3), merges organic phase, anhydrous sodium sulfate drying, evaporated under reduced pressure solvent, by residue silicagel column
Isolate and purify (dichloromethane：Methanol (volume ratio)=20:1) product 5 (white solid, 70mg, 0.18mmol, yield, are obtained：
57%).Analyze data is consistent with document (J.Med.Chem.2014,57,3205-3212).
Claims (10)
1. a kind of method for preparing chiral tetrahydropyran derivatives,
It comprises the following steps：
The first step：De- Boc protections reaction is carried out after compound 1 and compound 3 are mixed, obtains the steady of compound 6 and compound 7
Determine mixed solution；
Second step：With reducing agent reductive amination process is occurred into for the stable mixed solution in one pot, directly obtains product 5.
2. the method according to claim 1 for preparing chiral tetrahydropyran derivatives, it is characterised in that：The first step takes off
Boc protection reactions are carried out in the presence of solvent, and the solvent is trifluoroacetic acid or trifluoroacetic acid and another one or more solvent
Mixture, " another one or more solvent " be selected from ether solvent, aromatic solvent, alkane solvent, halogenated hydrocarbon solvent, acyl
One or more in amine solvent；The ether solvent be selected from ether, t-butyl methyl ether, isopropyl ether, 2- methyltetrahydrofurans,
One or more in tetrahydrofuran；One or more of the aromatic solvent in toluene, benzene；The alkane solvent is selected from
One or more in n-hexane, hexamethylene；The halogenated hydrocarbon solvent is selected from dichloromethane, symmetrical dichloroethanes, asymmetry two
One or more in chloroethanes；The amide solvent is selected from formamide, N,N-dimethylformamide, N, N- dimethylacetamides
One or more in amine, 1-METHYLPYRROLIDONE.
3. the method according to claim 1 for preparing chiral tetrahydropyran derivatives, it is characterised in that：Described in second step also
Former aminating reaction needs to carry out in the presence of amide solvent, and the amide solvent is selected from DMA, N, N-
One or more in dimethylformamide, N- methylacetamides, 1-METHYLPYRROLIDONE and formamide, the amide-type
Solvent is preferably dimethyl acetamide.
4. the method according to claim 1 for preparing chiral tetrahydropyran derivatives, it is characterised in that：Described in second step also
In former aminating reaction, the reducing agent is sodium triacetoxy borohydride or sodium cyanoborohydride.
5. the method according to claim 1 for preparing chiral tetrahydropyran derivatives, it is characterised in that：Described in second step also
Former aminating reaction is carried out in the presence of alkaloid, and the alkaloid is selected from triethylamine, diisopropyl ethyl amine, front three
One or more in amine, piperidines, piperazine, pyridine, morpholine, crassitude and pyrrolidines.
6. a kind of method for preparing chiral tetrahydropyran derivatives,
It comprises the following steps：
The first step：De- Boc protections reaction is carried out after compound 2 and compound 3 are mixed, obtains the steady of compound 6 and compound 7
Determine mixed solution；
Second step：With reducing agent reductive amination process is occurred into for the stable mixed solution in one pot, directly obtains product 5.
7. the method according to claim 6 for preparing chiral tetrahydropyran derivatives, it is characterised in that：The first step takes off
Boc protection reactions are carried out in the presence of solvent, and the solvent is trifluoroacetic acid or trifluoroacetic acid and another one or more solvent
Mixture, " another one or more solvent " be selected from ether solvent, aromatic solvent, alkane solvent, halogenated hydrocarbon solvent, acyl
One or more in amine solvent；The ether solvent be selected from ether, t-butyl methyl ether, isopropyl ether, 2- methyltetrahydrofurans,
One or more in tetrahydrofuran；One or more of the aromatic solvent in toluene, benzene；The alkane solvent is selected from
One or more in n-hexane, hexamethylene；The halogenated hydrocarbon solvent is selected from dichloromethane, symmetrical dichloroethanes, asymmetry two
One or more in chloroethanes；The amide solvent is selected from formamide, N,N-dimethylformamide, N, N- dimethylacetamides
One or more in amine, 1-METHYLPYRROLIDONE.
8. the method according to claim 6 for preparing chiral tetrahydropyran derivatives, it is characterised in that：Described in second step also
Former aminating reaction needs to carry out in the presence of amide solvent, and the amide solvent is selected from DMA, N, N-
One or more in dimethylformamide, N- methylacetamides, 1-METHYLPYRROLIDONE and formamide, the amide-type
Solvent is preferably dimethyl acetamide.
9. the method according to claim 6 for preparing chiral tetrahydropyran derivatives, it is characterised in that：Described in second step also
In former aminating reaction, the reducing agent is sodium triacetoxy borohydride or sodium cyanoborohydride.
10. the method according to claim 6 for preparing chiral tetrahydropyran derivatives, it is characterised in that：Described in second step
Reductive amination process is carried out in the presence of alkaloid, and the alkaloid is selected from triethylamine, diisopropyl ethyl amine, three
One or more in methylamine, piperidines, piperazine, pyridine, morpholine, crassitude and pyrrolidines.
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Citations (4)
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|---|---|---|---|---|
| CN102272136A (en) * | 2008-11-13 | 2011-12-07 | 默沙东公司 | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| CN103702562A (en) * | 2011-06-29 | 2014-04-02 | 默沙东公司 | Process for preparing chiral dipeptidyl peptidase-iv inhibitors |
| WO2016014324A1 (en) * | 2014-07-21 | 2016-01-28 | Merck Sharp & Dohme Corp. | Process for preparing chiral dipeptidyl peptidase-iv inhibitors |
| CN105399744A (en) * | 2015-12-17 | 2016-03-16 | 黄燕鸽 | Synthetic method for omarigliptin |
-
2016
- 2016-07-26 CN CN201610594375.4A patent/CN107652291B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102272136A (en) * | 2008-11-13 | 2011-12-07 | 默沙东公司 | Aminotetrahydropyrans as dipeptidyl peptidase-iv inhibitors for the treatment or prevention of diabetes |
| CN103702562A (en) * | 2011-06-29 | 2014-04-02 | 默沙东公司 | Process for preparing chiral dipeptidyl peptidase-iv inhibitors |
| CN103987388A (en) * | 2011-06-29 | 2014-08-13 | 默沙东公司 | Novel crystalline forms of a dipeptidyl peptidase-iv inhibitor |
| WO2016014324A1 (en) * | 2014-07-21 | 2016-01-28 | Merck Sharp & Dohme Corp. | Process for preparing chiral dipeptidyl peptidase-iv inhibitors |
| CN105399744A (en) * | 2015-12-17 | 2016-03-16 | 黄燕鸽 | Synthetic method for omarigliptin |
Non-Patent Citations (3)
| Title |
|---|
| TESFAYE BIFTU ET AL.: ""Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes"", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
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| 王欣 等: ""二肽基肽酶-4及其抑制剂的研究进展"", 《中国药学杂志》 * |
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