CN1774420B - Process for the preparation of N-substituted 2-cyanopyrrolidines - Google Patents
Process for the preparation of N-substituted 2-cyanopyrrolidines Download PDFInfo
- Publication number
- CN1774420B CN1774420B CN200480010135.0A CN200480010135A CN1774420B CN 1774420 B CN1774420 B CN 1774420B CN 200480010135 A CN200480010135 A CN 200480010135A CN 1774420 B CN1774420 B CN 1774420B
- Authority
- CN
- China
- Prior art keywords
- necessarily
- alkyl
- halogen
- substituted
- list
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 238000000034 method Methods 0.000 title claims abstract description 33
- -1 N-substituted 2-cyanopyrrolidines Chemical class 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 42
- 150000002367 halogens Chemical class 0.000 claims abstract description 35
- 150000003839 salts Chemical group 0.000 claims abstract description 19
- 239000002253 acid Substances 0.000 claims abstract description 15
- 150000001412 amines Chemical class 0.000 claims abstract description 12
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims abstract description 7
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 239000002585 base Substances 0.000 claims description 54
- 125000003630 glycyl group Chemical class [H]N([H])C([H])([H])C(*)=O 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 39
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 15
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 239000012634 fragment Substances 0.000 claims description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 11
- XLJMAIOERFSOGZ-UHFFFAOYSA-N cyanic acid Chemical compound OC#N XLJMAIOERFSOGZ-UHFFFAOYSA-N 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000003513 alkali Substances 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000003118 aryl group Chemical group 0.000 claims description 4
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 claims description 4
- 150000001721 carbon Chemical group 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 125000002837 carbocyclic group Chemical group 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 abstract description 2
- 238000006297 dehydration reaction Methods 0.000 abstract description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 abstract 3
- 238000002955 isolation Methods 0.000 abstract 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 125000002924 primary amino group Chemical class [H]N([H])* 0.000 description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 229940011051 isopropyl acetate Drugs 0.000 description 4
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 238000011049 filling Methods 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BNJMRELGMDUDDB-UHFFFAOYSA-N $l^{1}-sulfanylbenzene Chemical compound [S]C1=CC=CC=C1 BNJMRELGMDUDDB-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 125000006355 carbonyl methylene group Chemical group [H]C([H])([*:2])C([*:1])=O 0.000 description 2
- ZICQBHNGXDOVJF-UHFFFAOYSA-N diamantane Chemical compound C1C2C3CC(C4)CC2C2C4C3CC1C2 ZICQBHNGXDOVJF-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000007715 potassium iodide Nutrition 0.000 description 2
- 229960004839 potassium iodide Drugs 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- MEFKFJOEVLUFAY-UHFFFAOYSA-N (2,2,2-trichloroacetyl) 2,2,2-trichloroacetate Chemical compound ClC(Cl)(Cl)C(=O)OC(=O)C(Cl)(Cl)Cl MEFKFJOEVLUFAY-UHFFFAOYSA-N 0.000 description 1
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
- YAXWOADCWUUUNX-UHFFFAOYSA-N 1,2,2,3-tetramethylpiperidine Chemical compound CC1CCCN(C)C1(C)C YAXWOADCWUUUNX-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 1
- QKVSMSABRNCNRS-UHFFFAOYSA-N 4-(2-methylpropyl)morpholine Chemical compound CC(C)CN1CCOCC1 QKVSMSABRNCNRS-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- VCUFZILGIRCDQQ-KRWDZBQOSA-N N-[[(5S)-2-oxo-3-(2-oxo-3H-1,3-benzoxazol-6-yl)-1,3-oxazolidin-5-yl]methyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C1O[C@H](CN1C1=CC2=C(NC(O2)=O)C=C1)CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F VCUFZILGIRCDQQ-KRWDZBQOSA-N 0.000 description 1
- 125000004423 acyloxy group Chemical group 0.000 description 1
- 125000003670 adamantan-2-yl group Chemical group [H]C1([H])C(C2([H])[H])([H])C([H])([H])C3([H])C([*])([H])C1([H])C([H])([H])C2([H])C3([H])[H] 0.000 description 1
- 125000001118 alkylidene group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 239000002512 suppressor factor Substances 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pyrrole Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to a process for the preparation of a N-(N'-substituted glycyl)-2-cyanopyrrolidine comprising at least (a) reacting, in the presence of dimethylformamide, a compound of formula (V) wherein, independently of each other, X1 and X3 are halogen; X2 is halogen, OH, O-C(=O)-CH2X3, -O-SO2-(C1-8)alkyl or -O-SO2-(aryl), with L-prolinamide, followed by (b) reacting the resultant compound without isolation with a dehydration agent, optionally followed by (c) reacting, in the presence of a base, the resultant compound without isolation with an appropriate amine and (d) recovering the resultant cornpound in free form or in acid addition salt form.
Description
The present invention relates to the novel method of a kind of preparation N-(N '-substituted glycyl base)-2-Cyanopyrolidine and the compsn that mainly comprises N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines that can obtain according to this novel method.
Among the N-of free form or acid salt form (N '-substituted glycyl base)-2-Cyanopyrolidine, especially formula I those:
Wherein R is as giving a definition; Be valuable dipeptidyl peptidase-IV (DPP-IV) suppressor factor, for example be described among the WO98/19998.
The ordinary method of those compounds among preparation N-(N '-substituted glycyl base)-2-Cyanopyrolidine, especially following formula I comprises makes halogen (preferred chlorine or bromine) substituted (2-Cyanopyrolidine) carbonyl methylene radical and suitable amine reaction.Can obtain said substituted (2-Cyanopyrolidine) carbonyl methylene radical with the Trichloroacetic anhydride dehydration subsequently through making the reaction of halogen ethanoyl halogenide and L-prolineamide.This method has significant disadvantage, especially when considering the industrial production of N-(N '-substituted glycyl base)-2-Cyanopyrolidine because 1-halogen ethanoyl-2-Cyanopyrolidine midbody and directly precursor all be divided into pungent.In addition, this method causes potential waste problem and lower productive rate if a step needs the water-based aftertreatment.Reported a kind of substituting building-up process recently based on solid state chemistry; This process has been avoided free 1-halogen ethanoyl-2-Cyanopyrolidine; But be not suitable for amplification quantity production (N.Willand etc., Tetrahedron 58 (2002) 5741-5746) according to said this process of its author.Therefore, the needs of existence to improving one's methods.
Made us at present finding uncannily that 1-halogen ethanoyl-2-Cyanopyrolidine midbody can prepare with the mode that need not to separate said stimulator compound.Thereby said compound can directly further react with suitable amine.In addition, this novel method make all solvents can recycling and only by product be inorganic salt.This novel method is characterised in that total recovery is high and is suitable for industrial production.。
Thereby a target of the present invention is the method for preparing N-(N '-substituted glycyl base)-2-Cyanopyrolidine, and this method comprises at least:
(a) in the presence of N, make the compound and the reaction of L-prolineamide of formula V,
Wherein independently of each other, X
1And X
3Be halogen; X
2For halogen, OH, O-C (=O)-CH
2X
3,-O-SO
2-(C
1-8) alkyl or-O-SO
2-(aryl),
Subsequently
(b) make the gained compound without separating and the dewatering agent reaction, subsequently not necessarily
(c) in the presence of alkali, the gained compound is reacted without separating with suitable amine, and
(d) form with free form or acid salt reclaims the gained compound.
Work as X
2For-O-SO
2During-(aryl); Term " aryl " is meant that loop section has monocycle or the Bicyclic hydrocarbyl group that contains 6-12 carbon atom; For example phenyl, xenyl, naphthyl, tetrahydro naphthyl, every kind can not necessarily be replaced by 1-4 substituting group, such as substituted (C not necessarily
1-4) alkyl such as trifluoromethyl, halogen, hydroxyl, (C
1-4) alkoxyl group, aryl.Preferred this aromatic yl group is phenyl or substituted-phenyl.
Work as X
2For-O-SO
2-(C
1-8) during alkyl, term " alkyl " is meant the chain of straight chain or branching, it is not necessarily replaced the preferred fluorine of halogen, chlorine, bromine or iodine by 1-5 substituting group that is selected from halogen.Exemplary alkyl group comprises methyl, ethyl, propyl group, sec.-propyl, normal-butyl, the tertiary butyl, isobutyl-, trifluoromethyl.
In aforesaid method, amine or primary amine or secondary amine.The amine that this type is beneficial in organic chemistry in order to the synthetic drugs compound is conventionally known to one of skill in the art.Can be easily selected by the substituted suitable amine of one or two organic group, for example based on disclosed DPP-IV inhibitor structure in such as WO03/002596 by those skilled in the art.
Specifically, a target of the present invention is the method for preparing formula (I) compound, and this compound is free form or acid salt form:
Wherein R is:
A) R
1R
1aN (CH
2)
m-, wherein:
R
1Be pyridyl or pyrimidyl fragment, not necessarily by (C
1-4) alkyl, (C
1-4) alkoxyl group, halogen, trifluoromethyl, cyanic acid or the nitro list replaces or two independently the replacement; Or phenyl, not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or two independently the replacement;
R
1aBe hydrogen or (C
1-8) alkyl; And
M is 2 or 3;
B) (C
3-12) naphthenic base, the not necessarily quilt (C in the 1-position
1-3) replacement of hydroxyalkyl list;
C) R
2(CH
2)
n-, wherein perhaps
R
2Be phenyl, not necessarily by (C
1-4) alkyl, (C
1-4) alkoxyl group, halogen or phenyl sulphur list replaces or twoly independently replace or three replace independently, wherein phenyl sulphur is not necessarily replaced by the methylol list at phenyl ring; Or (C
1-8) alkyl; [3.1.1] two ring carbocyclic ring fragments are not necessarily by (C
1-8) alkyl list or polysubstituted; Pyridyl or naphthyl fragment are not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or two independently the replacement; Cyclohexenyl; Or not necessarily substituted adamantyl; And
N is 1-3; Perhaps
R
2Be phenoxy, not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or two independently the replacement; And
N is 2 or 3;
D) (R
3)
2CH (CH
2)
2-each R wherein
3Be phenyl independently, not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or two independently the replacement;
E) R
4(CH
2)
p-R wherein
4Be 2-oxa-pyrrolidyl or (C
2-4) alkoxyl group, and p is 2-4;
F) sec.-propyl, not necessarily quilt (C in the 1-position
1-3) replacement of hydroxyalkyl list; Perhaps
G) R
5, R wherein
5Be 2, the 3-indanyl; Pyrrolidyl or piperidyl fragment are not necessarily replaced by phenmethyl; [2.2.1] or [3.1.1] bicyclic carbocyclic fragment is not necessarily by (C
1-8) alkyl list or polysubstituted; Adamantyl; Substituted adamantyl; Or (C
1-8) alkyl, not necessarily by hydroxyl, methylol or phenyl list replacement or polysubstituted independently, this phenyl is not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or two independently the replacement;
This method comprises:
(a) in the presence of N, make the compound and the reaction of L-prolineamide of formula V,
Wherein independently of each other, X
1And X
3Be halogen; X
2For halogen, OH, O-C (=O)-CH
2X
3,-O-SO
2-(C
1-8) alkyl or-O-SO
2-(aryl),
Subsequently
(b) make the gained compound without separating and the dewatering agent reaction, preferably subsequently not necessarily
(c) in the presence of alkali, make the gained compound without separating and suitable amine reaction the compound of preferred formula (VI):
H
2NR (VI)
Wherein R is as the definition to formula (I), and
(d) form with free form or acid salt reclaims the gained compound.
Reaction (a) is carried out under inert atmosphere and in the presence of the mixture of N and other inert organic solvents or this kind solvent, preferred isopropyl acetate or ETHYLE ACETATE expediently.Temperature is preferably about 5 ℃-Yue 45 ℃, most preferably from about 10 ℃-Yue 35 ℃.The preferred excessive 2-20 mole % (V) that adopts.Preferably do not add alkali.Preferred X wherein
1And X
2All be the formula V compound of halogen, preferred chlorine of halogen and bromine; Preferred especially X
1And X
2Identical; And X most preferably
1And X
2All be chlorine.
Reaction (b) is carried out under inert atmosphere and in the presence of the mixture of inert organic solvents, preferred isopropyl acetate and N expediently.Temperature is preferably about 15 ℃-Yue 45 ℃, most preferably from about 12 ℃-Yue 35 ℃.Suitable dewatering agent is (halogen alkylidene group) dialkyl group ammonium halide, and wherein alkyl or alkylidene group are preferably the straight chain carbochain of 1-4 carbon atom, most preferable or methylene radical; Halogen is chlorine, bromine or iodine, most preferably chlorine.As dewatering agent most preferably Wei Lusimeier (Vilsmeier) reagent, i.e. (chlorine methylene radical) alkyl dimethyl ammonium chloride.The preferred dewatering agent that adopts excessive 2-20 mole %.Any subsequently excessive Wei Lusimeier reagent can make it to decompose through adding less water.
Reaction (c) is carried out under inert atmosphere expediently, thus the reaction product of (b) gained is added in the solution or suspension-s of amine compound in inert organic solvents of formula (VI) to the preferred 2-butanone of this solvent, acetone, acetonitrile or N.Temperature is preferably about 5 ℃-Yue 60 ℃, most preferably from about 10 ℃-Yue 35 ℃.The preferred potassiumiodide that adopts catalytic amount (for example 1-10%, preferred about 5%).The amine of formula (VI) uses with excessive 5-35 mole %, preferred excessive 10-25 mole %.Easily, the alkali that uses with 2-10 equivalent, preferred about 5.5 normal amounts can be alkaline carbonate or NaOH, preferred Na
2CO
3Or K
2CO
3, K most preferably
2CO
3
Reclaiming (d) comprises with the reaction mixture filtration, under reduced pressure except that desolvating and from the solvent that contains organic or inorganic alkali, making the crude product recrystallize expediently.In preferred embodiment, this solvent comprises the N-base, and for example 1,8-diaza-bicyclo [5.4.0] 11 carbon-7-alkene, tetramethyl guanidine, N (C
4H
9)
3, N (C
2H
5)
3, isobutyl-morpholine or tetramethyl piperidine.
The compound of formula (I) can exist with " free form " or with the acid salt form.Salt form can reclaim from " free form " with known method, and vice versa.Acid salt for example can be the salt of acceptable organic or inorganic acid in those pharmacy.Although preferred acid salt is the salt of hydrochloric acid, also can adopt the salt of methylsulphonic acid, sulfuric acid, phosphoric acid, Hydrocerol A, lactic acid and acetate.
" alkyl " and " alkoxyl group " can be the chain of straight chain or branching, and the latter's example is the sec.-propyl and the tertiary butyl.
The preferred as above definition of R a) or c).
R
1Preferred as above not necessarily substituted pyridyl or the pyrimidyl or the piperazinyl of definition.R
1aBe preferably hydrogen.R
2Be preferably not necessarily substituted phenyl or adamantyl.R
3Be preferably unsubstituted phenyl.R
4Be preferably the as above alkoxyl group of definition.R
5Be preferably as above the not necessarily substituted alkyl of definition, m is preferably 2, and n is preferably 1 or 2, and particularly 2.P is preferably 2 or 3, and particularly 3.
Pyridyl is preferably pyridine-2-base; Be preferably not replacement or mono-substituted, preferably on the 5-position, replace.The preferred position of pyrimidyl pyrimidine-2-base; Be preferably not replacement or mono-substituted, preferably on the 4-position, replace.As the substituting group of pyridyl and pyrimidyl, preferred halogen, cyanic acid and nitro, especially cyanic acid.
When being substituted, phenyl is preferably mono-substituted; Preferably replace the preferred chlorine of this halogen with halogen or methoxyl group.Preferably on 2-, 4-and/or 5-position, replace, particularly on the 4-position, replace.
(C
3-12) naphthenic base is preferably cyclopentyl or cyclohexyl.When being substituted, preferably replace with methylol.(C
2-4) alkoxyl group preferred 1 or 2 carbon atom, particularly methoxyl group.(C
1-8) alkoxyl group preferred 3 carbon atoms, particularly isopropoxy.Halogen is fluorine, chlorine, bromine or iodine, preferred fluorine, chlorine or bromine, particularly chlorine.(C
1-8) the preferred 1-6 of alkyl, more preferably 1-4 or 3-5, particularly 2 or 3 carbon atoms or methyl.(C
1-4) alkyl is preferably methyl or ethyl, particularly methyl.(C
1-3) hydroxyalkyl is preferably methylol.
As above not necessarily substituted [3.1.1] bicyclic carbocyclic fragment of definition is preferably dicyclo [3.1.1] heptan-2-base, is not necessarily replaced by methyl is two in the 6-position; Or dicyclo [3.1.1] heptan-3-base, not necessarily replaced by two methyl institutes three by a methyl and in the 6-position in the 2-position.As above not necessarily substituted [2.2.1] bicyclic carbocyclic fragment of definition is preferably dicyclo [2.2.1] heptan-2-base.
Naphthyl is preferably the 1-naphthyl.Cyclohexenyl is preferably hexamethylene-1-alkene-1-base.Diamantane is preferred unsubstituted or by one or more for example 2 substituted 1-of substituting group or 2-adamantyl.Preferred substituted is selected from alkyl;-OR
10Or-NR
11R
12, R wherein
10, R
11And R
12Be hydrogen, alkyl, C independently
1-8Alkyloyl, carbamyl; Or-CONR
13R
14, R wherein
13And R
14Be alkyl independently, do not replace or substituted aryl, and R
13And R
14One of be hydrogen or R extraly
13And R
14Represent C together
2-7Alkylidene group.
As above the not necessarily substituted pyridyl or the piperidyl fragment of definition are preferably pyridin-3-yl or piperidin-4-yl.When being substituted, preferred N-replaces.
Such formula (I) compound of free form or acid salt form very preferably, promptly wherein:
R is R
2(CH
2)
n-and R
2Be to replace adamantyl; And n is 0,1,2 or 3.
A kind of preferred group is with one of following formula (I) compound, the wherein bonding on end of the bridge of the substituting group on the adamantyl.
Preferred especially compound is the compound of the following formula of free form or acid salt form
Or
Wherein R ' is hydroxyl, C
1-7Alkoxyl group, C
1-8Alkyl acyloxy or R
R " " N-C (O) O-, wherein R
And R " " be respectively C
1-7Alkyl or phenyl, it is selected from C for unsubstituted or quilt
1-7Alkyl, C
1-7The substituting group of alkoxyl group, halogen and trifluoromethyl replaces, wherein R
Be hydrogen extraly, perhaps R wherein
And R " " be C
3-6Alkylidene group; R " be hydrogen; Perhaps R ' and R " be C independently
1-7Alkyl.
Particularly preferably be very much such formula (IA) compound of free form or acid salt form, promptly wherein R ' is hydroxyl and R " be hydrogen.This compound is called 1-[(3-hydroxyl-1-adamantyl) amino] ethanoyl-2 (S)-Cyanopyrolidine or LAF237.
Preferred suitable amine is formula (VI) compound of free form or acid salt form:
H
2NR (VI)
Wherein preferred R is with identical to those groups of formula (I) definition; Particularly R is R
2(CH
2)
n-and R
2For replacing adamantyl, particularly as above define; And n is 0,1,2 or 3.
Formula (I) compound exists with the form of optically active isomer or steric isomer; And can separate and recovery with routine techniques; Yet aforesaid method can production (I) compound, and this compound has N-(N '-substituted glycyl base)-2 (the S)-Cyanopyrolidines of high antimer purity (at least 95%).
Thereby; Another target of the present invention is the compsn of the N-that can obtain according to aforesaid method (N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines; 95%-99.9% is that N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and 5%-0.1% are N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines thus; Particularly 98%-99.9% is that N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines are 2%-0.1% thus; And preferably 98%-99.99% is that N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and 2%-0.01% are N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines thus, and especially preferably 99%-99.99% is that N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and 1%-0.01% are N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines thus.
In another embodiment of the present invention; Contained a kind of compsn; Pharmaceutical composition for example; Comprise N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines; 95%-99.9% is that N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and 5%-0.1% are N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines thus; Preferably N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines are that 95%-99.99% and N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines are 5%-0.01% thus; Most preferably 98%-99.99% is that N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and 2%-0.01% are N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines thus, and very preferably thus 99%-99.99% be that N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and 1%-0.01% are N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines.A preferred example is a kind of compsn; Pharmaceutical composition for example; Comprise N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines; N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines are that 99%-99.5% and N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines are 1%-0.5% thus, and perhaps N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines are that 99.2%-99.9% and N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines are 0.8%-0.1% thus.
Another target of the present invention is the compsn of the N-that can obtain according to aforesaid method (N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and/or N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines.
Preferably, the present invention is the compsn of a kind of N-of comprising (N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and/or N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines, and wherein by product is merely inorganic salt, preferably can obtain according to aforesaid method.
The present invention also is devoted to:
I) a kind of pharmaceutical composition comprises:
A) in one or more pharmacy acceptable vehicle and
B) at least a N-that can obtain according to aforesaid method (N '-substituted glycyl base)-2 (S)-Cyanopyrolidines.
Ii) a kind of pharmaceutical composition comprises:
A) in one or more pharmacy acceptable vehicle and
B) at least a N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and
C) at least a (halogen alkylidene group) dialkyl group ammonium halide between the 0.00001 weight %-5 weight %, preferred (chlorine methylene radical) alkyl dimethyl ammonium chloride.
Preferred N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines can obtain according to aforesaid method.
Preferred N-(N '-substituted glycyl base)-2 (S)-Cyanopyrolidines are those compounds of in aforesaid method, describing as preferred compound.
Embodiment
Embodiment 1)
The preparation of 1-[(3-hydroxyl-1-adamantyl) amino] ethanoyl-2 (S)-Cyanopyrolidine:
Step (a)
The reactor drum of being furnished with mechanical stirrer with 212g isopropyl acetate and 19.8g N filling 1500ml.With this reactor drum inerting.Under about 15 ℃ of IT (internal temperature), in 15 minutes, add the 125g chloroacetyl chloride, interpolation is adjusted to about 15 ℃ with IT after accomplishing, and in 1h, adds the solution of 110g L-prolineamide in the 304g N.With 18g isopropyl acetate flushing feed hopper.Reaction mixture is warming up to the about 35 ℃ of 1.5h of IT.
Step (b)
After being cooled to about 15 ℃, 142g Wei Lusimeier reagent portioning is added.This reaction mixture was stirred 1 hour down for about 25 ℃ at IT.Add 4.4g water down for maximum 25 ℃ at IT.
Step (c)
The reactor drum of being furnished with mechanical stirrer with 733g salt of wormwood, 194g3-hydroxylamino diamantane, 8.0g potassiumiodide and 880g 2-butanone filling 4.5l.This suspension-s is heated to about 35 ℃.Under this temperature, in 1.5h, add (thick (S)-1-chloracetyl-tetramethyleneimine-2-nitrile) of 937g step b).With 20g 2-butanone flushing feed hopper.Behind the restir 1h, this suspension-s is heated to about 70 ℃ of 30min.This temperature suspension filtered is also used warm 331g 2-butanone flush cake 3 times.To filtrate down concentrated in JT (jacket temperature) about 60 ℃ and decompression.
Step (d)
Under about 60 ℃ of JT, add 8.8g 1,8-diaza-bicyclo [5.4.0] 11 carbon-7-alkene and 44g Virahol and at the about 60 ℃ of stirring 30min down of IT.Gained suspension-s is cooled to about 40 ℃ of IT, and adds the 814g t-butyl methyl ether down for 40 ℃ at JT.This suspension-s is cooled to about 20 ℃ and under this temperature, stir 2h at least of IT, is cooled to-10 ℃-0 ℃ approximately then, stir 1h and filter.(v: v) mixture cleaned and filters " cake " twice with cold (approximately-10 ℃) Virahol of 168g and t-butyl methyl ether 1: 1.Under decompression and about 55 ℃ of JT with crude product (247g) drying.
Embodiment 2
The purifying of 1-[(3-hydroxyl-1-adamantyl) amino] ethanoyl-2 (S)-Cyanopyrolidine:
The reactor drum of being furnished with mechanical stirrer with 199g thick (1-[(3-hydroxyl-diamantane-1-base is amino)-ethanoyl]-tetramethyleneimine-2 (S)-nitrile) and 800g 2-butanone filling 750ml.With this mixture heating up to refluxing (95 ℃ of JT) and stirring 15min.This mixture is filtered in temperature (75 ℃ of the JT) reactor drum, cleaned filter cake with the 80g 2-butanone.IT is adjusted to 70 ℃ and add the suspension-s of 0.18g (1-[(3-hydroxyl-diamantane-1-base amino)-ethanoyl]-tetramethyleneimine-2 (S)-nitrile) in the 1.6g 2-butanone.Gained suspension-s is stirred 30min, the 2h internal cooling to IT50 ℃, then at 1h internal cooling to 30 ℃, at last at 1h internal cooling to 0 ℃, restir 1 hour.After this, suspension filtered is also washed crude product twice with the mixture of cold (0 ℃) 60.4g 2-butanone and 55.5g t-butyl methyl ether.Under decompression and about 50 ℃ of JT that product is dry.Fusing point is 148 ℃.
Claims (4)
1. the method for N-(N '-substituted glycyl base)-2-Cyanopyrolidine of formula (I) for preparing the form of form freely or acid salt,
Wherein R is:
A) R
1R
1aN (CH
2)
m-, wherein:
R
1Be not necessarily by (C
1-4) alkyl, (C
1-4) alkoxyl group, halogen, trifluoromethyl, cyanic acid or nitro list replace or disubstituted independently pyridyl or pyrimidyl fragment; Or not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or disubstituted independently phenyl; R
1aBe hydrogen or (C
1-8) alkyl; And
M is 2 or 3;
B) not necessarily in the 1-position by (C
1-3) mono-substituted (C of hydroxyalkyl
3-12) naphthenic base;
C) R
2(CH
2)
n-, wherein
R
2Be not necessarily by (C
1-4) alkyl, (C
1-4) alkoxyl group, halogen or phenyl sulfenyl list replaces or two independently the replacement or trisubstd phenyl independently, wherein the phenyl sulfenyl is not necessarily replaced by the methylol list at phenyl ring; Or (C
1-8) alkyl; Not necessarily by (C
1-8) alkyl list or polysubstituted [3.1.1] two ring carbocyclic ring fragments; Not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or disubstituted independently pyridyl or naphthyl fragment; Cyclohexenyl; Or not necessarily substituted adamantyl; And
N is 1-3; Perhaps
R
2Be not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or disubstituted independently phenoxy; And
N is 2 or 3;
D) (R
3)
2CH (CH
2)
2-, each R wherein
3Independently for not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or disubstituted independently phenyl;
E) R
4(CH
2)
p-, R wherein
4Be 2-oxa-pyrrolidyl or (C
2-4) alkoxyl group, and p is 2-4;
F) not necessarily in the 1-position by (C
1-3) the mono-substituted sec.-propyl of hydroxyalkyl; Perhaps
G) R
5, R wherein
5Be 2, the 3-indanyl; Not necessarily by substituted pyrrolidyl of phenmethyl or piperidyl fragment; Not necessarily by (C
1-8) alkyl list or polysubstituted [2.2.1]-or [3.1.1] bicyclic carbocyclic fragment; Adamantyl; Substituted adamantyl; Or not necessarily replaced or polysubstituted independently (C by hydroxyl, methylol or phenyl list
1-8) alkyl, above-mentioned phenyl is not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or two independently the replacement,
This method comprises at least:
(a) in the presence of N, make the compound and the reaction of L-prolineamide of formula V:
Wherein independently of each other, X
1And X
3Be halogen; X
2For halogen, OH, O-C (=O)-CH
2X
3,-O-SO
2-(C
1-8) alkyl or-O-SO
2-(aryl), subsequently
(b) make the gained compound without separating and the dewatering agent reaction that is selected from (halogen alkylidene group) dialkyl group ammonium halide, subsequently
(c) in the presence of alkali, make the gained compound without separating and suitable amine reaction, wherein amine is the compound of formula (VI):
H
2NR (VI)
Wherein R is as the definition to formula (I), and not necessarily
(d) form with form or acid salt freely reclaims the gained compound,
And
Work as X
2For-O-SO
2During-(aryl), term " aryl " is meant that loop section has the monocycle or the Bicyclic hydrocarbyl group that contain 6-12 carbon atom and can not necessarily be replaced by 1-4 substituting group for every kind.
2. according to the process of claim 1 wherein that (halogen alkylidene group) dialkyl group ammonium halide of step (b) is (chlorine methylene radical) alkyl dimethyl ammonium chloride.
3. according to the method for claim 1, comprising:
(a) in the presence of N, make the compound and the reaction of L-prolineamide of formula V,
X wherein
1Be halogen; X
2For halogen, OH, O-C (=O)-CH
2X
3,-O-SO
2-(C
1-8) alkyl or-O-SO
2-(aryl), subsequently
(b) make the gained compound without separating and the reaction of (chlorine methylene radical) alkyl dimethyl ammonium chloride, subsequently
(c) in the presence of alkali, the gained compound is reacted without the compound that separates with formula (VI):
H
2NR (VI)
Wherein R is as the definition to formula (I), and
(d) form with form or acid salt freely reclaims the gained compound.
4. according to each method among the claim 1-3, wherein R is R
2(CH
2)
n-and R
2It is substituted adamantyl; And n is 0,1,2 or 3.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0308854.9 | 2003-04-16 | ||
| GB0308854A GB0308854D0 (en) | 2003-04-16 | 2003-04-16 | Organic compounds |
| GB0311836A GB0311836D0 (en) | 2003-05-22 | 2003-05-22 | Process for the manufacture of organic compounds |
| GB0311836.1 | 2003-05-22 | ||
| PCT/EP2004/003980 WO2004092127A1 (en) | 2003-04-16 | 2004-04-15 | Process for the preparation of n-substituted 2-cyanopyrrolidines |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710090496 Division CN101037409B (en) | 2003-04-16 | 2004-04-15 | Process for the preparation of n-substituted 2-cyanopyrrolidines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1774420A CN1774420A (en) | 2006-05-17 |
| CN1774420B true CN1774420B (en) | 2012-05-30 |
Family
ID=9956928
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN200480010135.0A Expired - Fee Related CN1774420B (en) | 2003-04-16 | 2004-04-15 | Process for the preparation of N-substituted 2-cyanopyrrolidines |
| CN 200710090496 Expired - Fee Related CN101037409B (en) | 2003-04-16 | 2004-04-15 | Process for the preparation of n-substituted 2-cyanopyrrolidines |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200710090496 Expired - Fee Related CN101037409B (en) | 2003-04-16 | 2004-04-15 | Process for the preparation of n-substituted 2-cyanopyrrolidines |
Country Status (4)
| Country | Link |
|---|---|
| CN (2) | CN1774420B (en) |
| GB (1) | GB0308854D0 (en) |
| TN (1) | TNSN05261A1 (en) |
| ZA (1) | ZA200507396B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| HUP0900638A2 (en) * | 2009-10-07 | 2011-05-30 | Egyt Gyogyszervegyeszeti Gyar | Adducts of inorganic salts basea on vildaelitpin applicable for preparation of pharmaceutical compositions |
| CN103641761A (en) * | 2013-11-22 | 2014-03-19 | 沈阳化工大学 | Vildagliptin preparation method |
| CN104744334A (en) * | 2015-03-25 | 2015-07-01 | 合肥创新医药技术有限公司 | Preparation method for vildagliptin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1236361A (en) * | 1996-11-07 | 1999-11-24 | 诺瓦提斯公司 | N-substituted 2-cyanopyrodlidines |
| CN1329593A (en) * | 1998-12-10 | 2002-01-02 | 诺瓦提斯公司 | N-substituted 2-cyanopyrrolidines |
| US6380398B2 (en) * | 2000-01-04 | 2002-04-30 | Novo Nordisk A/S | Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
-
2003
- 2003-04-16 GB GB0308854A patent/GB0308854D0/en not_active Ceased
-
2004
- 2004-04-15 CN CN200480010135.0A patent/CN1774420B/en not_active Expired - Fee Related
- 2004-04-15 CN CN 200710090496 patent/CN101037409B/en not_active Expired - Fee Related
-
2005
- 2005-09-14 ZA ZA200507396A patent/ZA200507396B/en unknown
- 2005-10-14 TN TNP2005000261A patent/TNSN05261A1/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1236361A (en) * | 1996-11-07 | 1999-11-24 | 诺瓦提斯公司 | N-substituted 2-cyanopyrodlidines |
| CN1329593A (en) * | 1998-12-10 | 2002-01-02 | 诺瓦提斯公司 | N-substituted 2-cyanopyrrolidines |
| US6380398B2 (en) * | 2000-01-04 | 2002-04-30 | Novo Nordisk A/S | Therapeutically active and selective heterocyclic compounds that are inhibitors of the enzyme DPP-IV |
Non-Patent Citations (1)
| Title |
|---|
| CN 1329593 A,实施例1、权利要求1-5、说明书第2页最后一行－第4页第2行. |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101037409B (en) | 2013-03-27 |
| GB0308854D0 (en) | 2003-05-21 |
| TNSN05261A1 (en) | 2007-07-10 |
| CN101037409A (en) | 2007-09-19 |
| CN1774420A (en) | 2006-05-17 |
| ZA200507396B (en) | 2007-02-28 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1173443A (en) | Sulphonamides | |
| CN1281606C (en) | Nitrogen-containing heterocyclic compound | |
| US5659033A (en) | N-aminoalkylfluorenecarboxamides; a new class of dopamine receptor subtype specific ligands | |
| EP1956004A1 (en) | Quinoline derivatives and their use as 5-HT6 ligands | |
| CN1134151A (en) | Pyrazine carboxamide derivs., their production and their use in medicaments | |
| WO1995032190A2 (en) | Pharmaceutical diketopiperazine compounds | |
| IE58338B1 (en) | Pyrimidinyl-piperazine derivatives | |
| CN1429200A (en) | Anthranyl amides and their use as medicaments | |
| US4559349A (en) | Carboxamides | |
| IL91818A (en) | 2-substituted-9-halobenzyl-9h-purines, their preparation and pharmaceutical compositions containing them | |
| CA2404475A1 (en) | Phenylsulphonylpiperazinyl derivatives as 5-ht receptor ligands | |
| JP4672647B2 (en) | Process for producing N-substituted 2-cyanopyrrolidine | |
| US4940711A (en) | Antihypertensive N-piperazinylalkanoylanilides | |
| CN1774420B (en) | Process for the preparation of N-substituted 2-cyanopyrrolidines | |
| CA1056836A (en) | 2,6-disubstituted 2-phenylimino-imidazolidines their acid addition salts, pharmaceuticals containing same and processes for their production | |
| CN1463268A (en) | Process for prepn. of mesylates of piperzine derivatives | |
| US6242448B1 (en) | Trisubstituted-oxazole derivatives as serotonin ligands | |
| US4505913A (en) | Substituted anthranilamides and pharmaceutical preparations containing these compounds | |
| JP2008519832A (en) | Nitroindazole derivatives | |
| CN1023480C (en) | 3-aryl-5-alkylthio-4h-1,2,4-triazoles derivatives and prepn. method therefor | |
| NO882065L (en) | DIARYLALKYL-SUBSTITUTED ALKYLAMINES, PROCEDURE FOR THE PREPARATION OF THEM, USE OF THEM, SUCH AS SUBSTANCES CONTAINING THEM. | |
| CN1103338C (en) | Heterocyclic compounds for treating myocardial ischaemia | |
| JPH01203379A (en) | Further hydrogenated 1-benzooxacycloalkyl pyridine carboxylic acids | |
| US20040171683A1 (en) | Method and materials for treatment of Alzheimer's disease | |
| CN1030077A (en) | Famotidine pyridine polymorphic form and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C56 | Change in the name or address of the patentee |
Owner name: NOVARTIS CO., LTD. Free format text: FORMER NAME: NOVARTIS AG |
|
| CP01 | Change in the name or title of a patent holder |
Address after: Basel, Switzerland Patentee after: NOVARTIS AG Address before: Basel, Switzerland Patentee before: Novartis AG |
|
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20120530 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |