CN101037409B - Process for the preparation of n-substituted 2-cyanopyrrolidines - Google Patents
Process for the preparation of n-substituted 2-cyanopyrrolidines Download PDFInfo
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- CN101037409B CN101037409B CN 200710090496 CN200710090496A CN101037409B CN 101037409 B CN101037409 B CN 101037409B CN 200710090496 CN200710090496 CN 200710090496 CN 200710090496 A CN200710090496 A CN 200710090496A CN 101037409 B CN101037409 B CN 101037409B
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- halogen
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- cyanopyrolidines
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title abstract description 7
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical class N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 37
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 150000002367 halogens Chemical class 0.000 claims abstract description 27
- -1 N-(N'-substituted glycyl)-2-cyanopyrrolidine Chemical class 0.000 claims abstract description 21
- 150000003839 salts Chemical group 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 14
- 150000001412 amines Chemical class 0.000 claims abstract description 11
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 9
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims abstract description 5
- 239000002585 base Substances 0.000 claims description 51
- 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 28
- 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
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 229910052794 bromium Inorganic materials 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims description 2
- 125000002619 bicyclic group Chemical group 0.000 claims description 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 230000018044 dehydration Effects 0.000 abstract description 2
- 238000006297 dehydration reaction Methods 0.000 abstract description 2
- 238000002955 isolation Methods 0.000 abstract 2
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000003545 alkoxy group Chemical group 0.000 description 14
- 239000000203 mixture Substances 0.000 description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 11
- 239000000725 suspension Substances 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 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
- 125000004076 pyridyl group Chemical group 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
- 125000000714 pyrimidinyl group Chemical group 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 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
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 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
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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
- QQVDYSUDFZZPSU-UHFFFAOYSA-M chloromethylidene(dimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)=CCl QQVDYSUDFZZPSU-UHFFFAOYSA-M 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 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
- 238000011049 filling Methods 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 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
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000005936 piperidyl group Chemical group 0.000 description 2
- 235000007715 potassium iodide Nutrition 0.000 description 2
- 229960004839 potassium iodide Drugs 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
- 0 *NCC(N(CCC1)[C@@]1C#N)=O Chemical compound *NCC(N(CCC1)[C@@]1C#N)=O 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
- 238000013019 agitation Methods 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
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 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
- 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
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- 238000010992 reflux Methods 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 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
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 compound in free form or in acid addition salt form.
Description
The present invention relates to the novel method of a kind of N-of preparation (N '-substituted glycyl base)-2-Cyanopyrolidine and the composition 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) inhibitor, 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 (2-Cyanopyrolidine) carbonyl methylene radical that halogen (preferred chlorine or bromine) replaces and suitable amine reaction.Can obtain subsequently (2-Cyanopyrolidine) carbonyl methylene radical of described replacement with the Trichloroacetic anhydride dehydration by making the reaction of halogen ethanoyl halogenide and L-prolineamide.This method has significant shortcoming, especially when considering the industrial production of N-(N '-substituted glycyl base)-2-Cyanopyrolidine, because 1-halogen ethanoyl-2-Cyanopyrolidine intermediate and direct precursor thereof all are divided into pungent.In addition, if the method needs the water-based aftertreatment in individual step, cause potential waste problem and lower productive rate.Reported recently a kind of substituting building-up process 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., Tetrahedron58 (2002) 5741-5746) according to described this process of its author.Therefore, the needs of existence to improving one's methods.
Made us now finding uncannily that 1-halogen ethanoyl-2-Cyanopyrolidine intermediate can prepare in the mode that need not to separate described stimulator compound.Thereby described compound can directly further react with the amine that suits.In addition, this novel method make all solvents can recirculation 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 the method comprises at least:
(a) in the presence of dimethyl formamide, make 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 " refers to 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 (the C that not necessarily replaces
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 " refers to 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 class is beneficial in organic chemistry in order to the synthetic drugs compound is conventionally known to one of skill in the art.The suitable amine that is replaced by one or two organic group can easily be selected by those skilled in the art, for example based on disclosed DPP-IV inhibitor structure in such as WO03/002596.
Specifically, a target of the present invention is the method for preparation 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
1Pyridyl or pyrimidyl fragment, not necessarily by (C
1-4) alkyl, (C
1-4) alkoxyl group, halogen, trifluoromethyl, cyano group or the nitro list replaces or two replacement independently; Or phenyl, not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or independently two replacements;
R
1aHydrogen or (C
1-8) alkyl; And
M is 2 or 3;
B) (C
3-12) cycloalkyl, not necessarily at 1-position quilt (C
1-3) replacement of hydroxyalkyl list;
C) R
2(CH
2)
n-, wherein or
R
2Phenyl, not necessarily by (C
1-4) alkyl, (C
1-4) alkoxyl group, halogen or phenyl sulfenyl list replaces or twoly independently replace or three replace independently, wherein the phenyl sulfenyl 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 independently two replacements; Cyclohexenyl; Or the adamantyl that not necessarily replaces; And
N is 1-3; Perhaps
R
2Phenoxy group, not necessarily by (C
1-4) alkyl, (C
1-4) replacement of alkoxy or halogen list or independently two replacements; 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 independently two replacements;
E) R
4(CH
2)
p-R wherein
42-oxa-pyrrolidyl or (C
2-4) alkoxyl group, and p is 2-4;
F) sec.-propyl is not necessarily at 1-position quilt (C
1-3) replacement of hydroxyalkyl list; Perhaps
G) R
5, R wherein
5It is 2,3-indanyl; Pyrrolidyl or piperidyl fragment are not necessarily replaced by phenmethyl; [2.2.1]-or [3.1.1] bicyclic carbocyclic fragment, not necessarily by (C
1-8) alkyl list or polysubstituted; Adamantyl; The adamantyl that replaces; 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 independently two replacements;
The method comprises:
(a) in the presence of dimethyl formamide, make 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 dimethyl formamide and other inert organic solvents or this kind solvent, preferred isopropyl acetate or ethyl acetate expediently.Temperature is preferably about 5 ℃-Yue 45 ℃, most preferably from about 10 ℃-Yue 35 ℃.Excessive 2-20 % by mole (V) of preferred employing.Preferably do not add alkali.Preferred X wherein
1And X
2All be formula (V) compound of halogen, the preferred chlorine of halogen and bromine; X particularly preferably
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 dimethyl formamide 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 the carbochain of the preferred straight chain of 1-4 carbon atom, most preferable or methylene radical; Halogen is chlorine, bromine or iodine, most preferably chlorine.As dewatering agent most preferably Vilsmeier reagent, i.e. (chlorine methylene radical) alkyl dimethyl ammonium chloride.The preferred dewatering agent that adopts excessive 2-20 % by mole.Any excessive Vilsmeier reagent can make it to decompose by adding a small amount of water subsequently.
Reaction (c) is carried out under inert atmosphere expediently, reaction products addition with (b) gained arrives in the solution or suspension of amine compound in inert organic solvents of formula (VI) the preferred 2-butanone of this solvent, acetone, acetonitrile or dimethyl formamide thus.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) is with excessive 5-35 % by mole use, preferred excessive 10-25 % by mole.Easily, the alkali that uses with the amount of 2-10 equivalent, preferred about 5.5 equivalents can be alkaline carbonate or NaOH, preferred Na
2CO
3Or K
2CO
3, K most preferably
2CO
3
Recovery (d) comprises expediently reaction mixture filtration, under reduced pressure desolventizing and make the crude product recrystallize from the solvent that contains organic or inorganic alkali.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, citric acid, lactic acid and acetic acid.
" alkyl " and " alkoxyl group " can be the chain of straight chain or branching, and the latter's example is sec.-propyl and the tertiary butyl.
R preferably as defined above a) or c).
Preferred pyridyl or pyrimidyl or the piperazinyl that not necessarily replaces as defined above.R
1aBe preferably hydrogen.R
2Be preferably the phenyl or the adamantyl that not necessarily replace.R
3Be preferably unsubstituted phenyl.R
4Be preferably as defined above alkoxyl group.R
5Be preferably as defined above the alkyl that not necessarily replaces, m is preferably 2, n and 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 replace in the 5-position.The preferred position of pyrimidyl pyrimidine-2-base; Be preferably not replacement or mono-substituted, preferably replace in the 4-position.As the substituting group of pyridyl and pyrimidyl, preferred halogen, cyano group and nitro, especially cyano group.
When being substituted, phenyl is preferably mono-substituted; Preferably with halogen or methoxy substitution, the preferred chlorine of this halogen.Preferably replace at 2-, 4-and/or 5-position, particularly replace in the 4-position.
(C
3-12) cycloalkyl 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.
[3.1.1] bicyclic carbocyclic fragment that not necessarily replaces as defined above 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.[2.2.1] bicyclic carbocyclic fragment that not necessarily replaces as defined above 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 1-or 2-adamantyls that substituting group replaces.Preferred substituting group 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
14The aryl that is alkyl independently, does not replace or replace, and R
13And R
14One of be hydrogen or R extraly
13And R
14Represent together C
2-7Alkylidene group.
The pyridyl or the piperidyl fragment that not necessarily replace as defined above 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, namely wherein: R is R
2(CH
2)
n-and R
2To 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.
Particularly preferred compound is the compound of the following formula of free form or acid salt form
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.
Very particularly preferably be such formula (IA) compound of free form or acid salt form, namely wherein R ' is hydroxyl and R " for 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 defined above; 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 composition 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 particularly 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 composition; 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 composition; 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 composition 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 composition of a kind of N-of comprising (N '-substituted glycyl base)-2 (S)-Cyanopyrolidines and/or N-(N '-substituted glycyl base)-2 (R)-Cyanopyrolidines; wherein by product only is inorganic salt, preferably can obtain according to aforesaid method.
The present invention also is devoted to:
I) a kind of pharmaceutical composition comprises:
A) acceptable vehicle in one or more pharmacy, 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) acceptable vehicle in one or more pharmacy, 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 0.00001 % by weight-5 % by 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 describing as preferred compound in aforesaid method.
Embodiment
Embodiment 1)
1-[(3-hydroxyl-1-adamantyl) amino] preparation of ethanoyl-2 (S)-Cyanopyrolidine:
Step (a)
The reactor of being furnished with mechanical stirrer with 212g isopropyl acetate and 19.8g dimethyl formamide filling 1500ml.With this reactor inerting.Under about 15 ℃ of IT (internal temperature), in 15 minutes, add the 125g chloroacetyl chloride, after interpolation is finished, IT is adjusted to about 15 ℃, and in 1h, adds the solution of 110gL-prolineamide in the 304g dimethyl formamide.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 ℃, 142gVilsmeier reagent portioning is added.This reaction mixture was stirred 1 hour down about 25 ℃ of IT.At the maximum 25 ℃ of lower 4.4g water that add of IT.
Step (c)
The reactor 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 is heated to about 35 ℃.Under this temperature, in 1.5h, add 937g step b) (thick (S)-1-chloracetyl-tetramethyleneimine-2-nitrile).With 20g 2-butanone flushing feed hopper.Behind the restir 1h, this suspension is heated to about 70 ℃ of 30min.This temperature suspension filtered is also used warm 331g2-butanone flush cake 3 times.At JT (jacket temperature) about 60 ℃ and decompression is lower that filtrate is concentrated.
Step (d)
Under about 60 ℃ of JT, add 8.8g1,8-diaza-bicyclo [5.4.0] 11 carbon-7-alkene and 44g Virahol and at the about 60 ℃ of lower 30min that stir of IT.Gained suspension is cooled to about 40 ℃ of IT, and the JT40 ℃ of lower 814g t-butyl methyl ether of adding.This suspension is cooled to about 20 ℃ and stir at least 2h under this temperature of IT, then is cooled to-10 ℃-0 ℃ approximately, 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
1-[(3-hydroxyl-1-adamantyl) amino] purifying of ethanoyl-2 (S)-Cyanopyrolidine:
With thick (1-[(3-hydroxyl-diamantane-1-base the is amino)-ethanoyl of 199g]-tetramethyleneimine-2 (S)-nitrile) and the 800g2-butanone load the reactor that 750ml is furnished with mechanical stirrer.With this mixture heating up to refluxing (JT95 ℃) and stirring 15min.This mixture is filtered in temperature (JT75 ℃) reactor, cleaned filter cake with the 80g2-butanone.With IT be adjusted to 70 ℃ and add 0.18g (1-[(3-hydroxyl-diamantane-1-base amino)-ethanoyl]-tetramethyleneimine-2 (S)-nitrile) suspension in the 1.6g2-butanone.With gained suspension agitation 30min, in 2h, be cooled to IT50 ℃, then in 1h, be cooled to 30 ℃, in 1h, be cooled to 0 ℃ at last, restir 1 hour.After this, suspension filtered is also washed crude product twice with the mixture of cold (0 ℃) 60.4g2-butanone and 55.5g t-butyl methyl ether.Under decompression and about 50 ℃ of JT that product is dry.Fusing point is 148 ℃.
Claims (2)
1. the method for N-(N '-substituted glycyl base)-2-Cyanopyrolidine of following formula for preparing the form of form freely or acid salt,
Wherein R ' is hydroxyl and R " be hydrogen; The method comprises at least:
(a) in the presence of dimethyl formamide, make 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, wherein dewatering agent is (halogen alkylidene group) dialkyl group ammonium halide, and wherein alkyl or alkylidene group are the carbochain of 1-4 carbon atom, and halogen is chlorine, bromine or iodine,
(c) in the presence of alkali, the gained compound is reacted without the amine that separates with following formula,
Wherein R ' is hydroxyl and R " be hydrogen, and
(d) form with freely form or acid salt reclaims the gained compound,
Wherein said aryl is that loop section has monocycle or the Bicyclic hydrocarbyl group that contains 6-12 carbon atom.
2. according to claim 1 method, wherein the dewatering agent of step (b) is (chlorine methylene radical) alkyl dimethyl ammonium chloride.
Applications Claiming Priority (4)
| 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 |
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|---|---|---|---|
| CN200480010135.0A Division CN1774420B (en) | 2003-04-16 | 2004-04-15 | Process for the preparation of N-substituted 2-cyanopyrrolidines |
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| CN101037409B true CN101037409B (en) | 2013-03-27 |
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ID=9956928
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| CN 200710090496 Expired - Fee Related CN101037409B (en) | 2003-04-16 | 2004-04-15 | Process for the preparation of n-substituted 2-cyanopyrrolidines |
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|---|---|
| CN (2) | CN1774420B (en) |
| GB (1) | GB0308854D0 (en) |
| TN (1) | TNSN05261A1 (en) |
| ZA (1) | ZA200507396B (en) |
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| 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,说明书第2页最后1行至第4页第2行,权利要求1-5，实施例1-12. |
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|---|---|
| CN1774420A (en) | 2006-05-17 |
| CN1774420B (en) | 2012-05-30 |
| GB0308854D0 (en) | 2003-05-21 |
| TNSN05261A1 (en) | 2007-07-10 |
| ZA200507396B (en) | 2007-02-28 |
| CN101037409A (en) | 2007-09-19 |
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