CN102491928A - Method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine - Google Patents
Method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine Download PDFInfo
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- CN102491928A CN102491928A CN2011104134478A CN201110413447A CN102491928A CN 102491928 A CN102491928 A CN 102491928A CN 2011104134478 A CN2011104134478 A CN 2011104134478A CN 201110413447 A CN201110413447 A CN 201110413447A CN 102491928 A CN102491928 A CN 102491928A
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- chloracetyl
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- pyrrolidine
- cyanic acid
- proline
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- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title claims abstract description 116
- 238000000034 method Methods 0.000 title claims abstract description 43
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000002360 preparation method Methods 0.000 claims abstract description 30
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 22
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims abstract description 16
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims abstract description 12
- 235000011114 ammonium hydroxide Nutrition 0.000 claims abstract description 10
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims abstract description 9
- 229930182821 L-proline Natural products 0.000 claims abstract description 9
- 229960002429 proline Drugs 0.000 claims abstract description 9
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims abstract description 9
- VTVJMWZZVJSEMO-BYPYZUCNSA-N (2s)-pyrrolidine-2-carbonyl chloride Chemical compound ClC(=O)[C@@H]1CCCN1 VTVJMWZZVJSEMO-BYPYZUCNSA-N 0.000 claims abstract description 8
- 238000006297 dehydration reaction Methods 0.000 claims abstract description 6
- 238000005917 acylation reaction Methods 0.000 claims abstract description 3
- 230000035484 reaction time Effects 0.000 claims description 16
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 claims description 10
- 229910019213 POCl3 Inorganic materials 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- KDVAQFIPIMCVRJ-LURJTMIESA-N ClCC(=O)N1[C@@H](CCC1)NC=O Chemical compound ClCC(=O)N1[C@@H](CCC1)NC=O KDVAQFIPIMCVRJ-LURJTMIESA-N 0.000 claims description 4
- 229960001701 chloroform Drugs 0.000 claims description 2
- 239000003814 drug Substances 0.000 abstract description 3
- YKDRUBGIBPCRBH-YFKPBYRVSA-N (2s)-1-(2-chloroacetyl)pyrrolidine-2-carboxamide Chemical compound NC(=O)[C@@H]1CCCN1C(=O)CCl YKDRUBGIBPCRBH-YFKPBYRVSA-N 0.000 abstract 1
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 abstract 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- WBLIXGSTEMXDSM-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH2] WBLIXGSTEMXDSM-UHFFFAOYSA-N 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000009413 insulation Methods 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- -1 prolyl chlorine Chemical compound 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- 230000004069 differentiation Effects 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 229940124213 Dipeptidyl peptidase 4 (DPP IV) inhibitor Drugs 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000003603 dipeptidyl peptidase IV inhibitor Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
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- Plural Heterocyclic Compounds (AREA)
Abstract
The invention provides a method for preparing (2S)-N-chloracetyl-2-cyano-group pyrrolidine, which belongs to the technical field of chemical medicine midbody preparation methods. The preparation method comprises the steps: (1) L-proline and thionyl chloride generate acylation reaction to obtain L-proline chloride; (2) the L-proline chloride and ammonia water generate reaction to produce L-proline amide; (3) the L-proline amide and chloroacetyl chloride generate reaction to obtain (2S)-N-chloracetyl-2-carbamoyl pyrrole; and (4) (2S)-N-chloracetyl-2-carbamoyl pyrrolidine and phosphorus oxychloride generate dehydration reaction under low temperature condition to obtain the (2S)-N-chloracetyl-2-cyano-group pyrrolidine. The method has the advantages of saving material cost, being simple in technological process, moderate in reaction condition, low in operation difficulty, convenient in aftertreatment, stable in quality and suitable for mass industrial production, having operability, and improving yield of prepared products by a large margin.
Description
Technical field
The invention belongs to medicine intermediate preparation method technical field, be specifically related to the method for a kind of preparation (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine.
Background technology
(2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is the key intermediate in row spit of fland, hypoglycemic kind new medicine Victor.The synthetic way that adopts is at present all had relatively high expectations to production unit, and cost is high; And what obtain is (the 2S)-N-chloracetyl-2-cyanic acid Pyrrolidine of low yield, and the Related domestic documents report discloses the study on the synthesis in row spit of fland, dipeptidyl peptidase-iv inhibitor Victor; It uses the acetylize of L-proline(Pro) elder generation, after use expensive DCC, the time standby POCl3 dehydration of dehydration obtains (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine; Its yield very low cost is too expensive, is difficult to realize suitability for industrialized production; External in addition pertinent literature US6166063, WO0034241, Beilstein Journal of Organic Chemistry 2008,4; No.20.J.Med.Chem.2002,45,2362-2365; Journal of Medicinal Chemistry, 2003, Vol.46; No.13 2775, and US20080167479 etc. disclose the synthetic report of (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine, all are the acetylizes of prolineamide elder generation; The expensive trifluoroacetic anhydride of time standby of dehydration is perhaps used expensive DCC and is done amidation, and very low cost is too expensive to be difficult to realize its yield of suitability for industrialized production; Be difficult to realize suitability for industrialized production, the synthetic chloride of L-prolineamide in addition, bibliographical information is not seen in back amination.
Summary of the invention
A kind of preparing method's cost that the objective of the invention is in order to solve (2S)-N-chloracetyl in the prior art-2-cyanic acid Pyrrolidine is high; Operation easier is big; Be difficult to realize industrialized shortcoming, the method for a kind of preparation (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is provided.
Technical scheme of the present invention is following:
The method of a kind of preparation (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine may further comprise the steps:
(1) L-proline(Pro) and sulfur oxychloride generation acylation reaction obtain L-prolyl villaumite hydrochlorate, and temperature of reaction is-10 ℃～110 ℃, and the reaction times is 1～10 hour, and reaction formula is following:
(2) L-prolyl chlorine and ammoniacal liquor react and generate the L-prolineamide, and temperature of reaction is-10 ℃～40 ℃, and the reaction times is 1～10 hour, and reaction formula is following:
(3) (3) L-prolineamide and chloroacetyl chloride react and obtain (2S)-N-chloracetyl-2-formamido-pyrroles, and temperature of reaction is 0 ℃～70 ℃, and the reaction times is 1～10 hour, and reaction formula is following:
(4) (2S)-N-chloracetyl-2-formamido-Pyrrolidine generates (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine with POCl3 generation dehydration reaction under coldcondition; Temperature of reaction is-15 ℃～30 ℃; Reaction times is 1～10 hour, and reaction formula is following:
The method of a kind of preparation (2S) described in the technique scheme-N-chloracetyl-2-cyanic acid Pyrrolidine, wherein, the described solvent of step (1) is methylene dichloride, trichloromethane, toluene or benzene.
The method of a kind of preparation (2S) described in the technique scheme-N-chloracetyl-2-cyanic acid Pyrrolidine, wherein, the mol ratio of L-proline(Pro) and sulfur oxychloride is 1 in the step (1): (1～4); Preferred L-proline(Pro) and sulfur oxychloride mol ratio are 1: 2.
The method of a kind of preparation (2S) described in the technique scheme-N-chloracetyl-2-cyanic acid Pyrrolidine, wherein, step (2) described L-prolyl chlorine and ammoniacal liquor mol ratio are 1: (5～30); Preferred L-prolyl chlorine and ammoniacal liquor mol ratio are 1: 10.
The method of a kind of preparation (2S) described in the technique scheme-N-chloracetyl-2-cyanic acid Pyrrolidine, wherein, the mol ratio of described L-prolineamide of step (3) and chloroacetyl chloride is 1: (1～2); The mol ratio of preferred L-prolineamide and chloroacetyl chloride is 1: 1.2.
The method of a kind of preparation (2S) described in the technique scheme-N-chloracetyl-2-cyanic acid Pyrrolidine, wherein, the temperature of reaction of described L-prolineamide of step (3) and chloroacetyl chloride is 0 ℃～70 ℃, the reaction times is 1～2 hour.
The method of a kind of preparation (2S) described in the technique scheme-N-chloracetyl-2-cyanic acid Pyrrolidine, wherein, the temperature of reaction of described L-prolineamide of step (3) and chloroacetyl chloride is 10 ℃～70 ℃, the reaction times is 1 hour.
The method of a kind of preparation (2S) described in the technique scheme-N-chloracetyl-2-cyanic acid Pyrrolidine, wherein, the mol ratio of described (the 2S)-N-chloracetyl of step (4)-2-formamido-Pyrrolidine and POCl3 is 1: (1～5); Preferably the mol ratio of (2S)-N-chloracetyl-2-formamido-Pyrrolidine and POCl3 is 1: 2.
The method of a kind of preparation (2S) described in the technique scheme-N-chloracetyl-2-cyanic acid Pyrrolidine; Wherein, The temperature of reaction of described (the 2S)-N-chloracetyl of step (4)-2-formamido-Pyrrolidine and POCl3 is-5 ℃～30 ℃, and the reaction times is 1～8 hour.
The present invention has following beneficial effect:
With low cost; Technical process is simple relatively, and reaction conditions is gentle, and operation easier is little, has more operability; Convenient post-treatment; The product yield of preparation increases substantially, and steady quality is suitable for large-scale commercial prodn.
Embodiment:
For making technical scheme of the present invention be convenient to understand, the present invention is further described below in conjunction with specific embodiment.
Embodiment 1: a kind of preparation (2S)-N
The method of-chloracetyl-2-cyanic acid Pyrrolidine
(1), in the 100ml four-hole boiling flask, add 10g L-proline(Pro), the 50ml methylene dichloride is opened and is stirred, and is cooled to 0～5 ℃; Keep this temperature and slowly drip the 20.7g sulfur oxychloride, finish and be warming up to backflow, be incubated 1 hour; Reaction is finished, and 30 ℃ of evaporated under reduced pressure solvents obtain 15gL-prolyl chlorine.
(2), keep 0～5 ℃ and slowly be added drop-wise to above-mentioned 15gL-prolyl chlorine in the ammoniacal liquor of 100g 20%, under-10 ℃～40 ℃ conditions, reacted 1～10 hour, reaction is finished; With methylene dichloride 100ml*6 extraction six times, merge organic layer, drying; Suction filtration; Filtrate 30 ℃ of decompression precipitations to the dried 8gL-prolineamide that obtains, Mp:96～98 ℃, [α] D
20-106
0(c=2C
2H
5OH)
(3), add the 100ml THF to above-mentioned 8gL-prolineamide, open and stir, under the room temperature condition, drip the chloroacetyl chloride of 9.5g; Finish and be warming up to the insulation 1 hour that refluxes, be cooled to below 20 ℃, keep below 10 ℃ being added drop-wise to it slowly in the frozen water of 50g at once; The back merges organic layer, drying with the ethyl acetate extraction of 100ml*3; Suction filtration, 30 ℃ of evaporated under reduced pressure solvents obtain 13g (2S)-N-chloracetyl-2-formamido-pyrroles.
Mp：133～137℃；[α]D
25-163.3(c?1.00，CHCl3)；IR(KBr，cm
-1)：3383，3156，2982，2942，2885，2765；
1H?NMR(300MHz，CDCl3+CD30D)2.0-2.2(m，4H)，3.55-3.75(m，2H)，4.06(m，0.4H，CH2Cl)，4.16(m，1.6H，CH2Cl)，4.47(m，1H，CHCONH2)；13C?NMR(75MHz，CDCl3)δ24.9，28.1，42.0，47.4，60.1，166.3，173.3；m/z?191.1[M+1]
(4), add 30ml DMF to above-mentioned 13g (2S)-N-chloracetyl-2-formamido-pyrroles and stir to dissolve clearly, keep 0～5 ℃ and slowly drip the 21g POCl3, finish and keep 0～5 ℃ of insulation 2 hours; Reaction is finished, and slowly joins in the frozen water of 120ml, and the back is with the ethyl acetate extraction of 100ml*5; Merge organic layer, drying, suction filtration; 30 ℃ of evaporated under reduced pressure solvents obtain 9.7g (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine
HPLC?Purity：99.25％；mp?52～53℃；IR(KBr，cm-1)：3304，2992，2953，2888，2242，1662，1424；1H?NMR(300MHz，CDCl3)δ(4：1?mixture?of?trans/cis?amide?rotamers)2.1-2.4(m，4H)，3.56-3.64(m，1H)，3.69-3.76(m，1H)，4.02-4.21(m，0.4H，CH2Cl)，4.06(s，1.6H，CH2Cl)，4.76(m，0.8H，CHCN)，4.86(m，0.2H，CHCN)；13CNMR(75MHz，CDCl3)δ22.7，24.6，25.1，29.9，32.4，41.6，46.4，46.7，46.9，47.0，117.8，164.7，165.2；m/z?173.1[M+1]
Embodiment 2: a kind of preparation (2S)-N
The method of-chloracetyl-2-cyanic acid Pyrrolidine
Present embodiment is identical with the process of embodiment 1, and difference is: the insulation in the step (1) in the preparation prolyl chlorine step refluxes and made into 10 hours in 1 hour, and yield can be accomplished 15gL-prolyl chlorine in the same old way, and below raw material does not influence single step reaction.
Embodiment 3: a kind of preparation (2S)-N
The method of-chloracetyl-2-cyanic acid Pyrrolidine
Present embodiment is identical with the process of embodiment 1; Difference is: with prolyl chlorine in the step (2) be added drop-wise in the ammoniacal liquor temperature of reaction make 0 ℃～40 ℃ into; Reaction times made into 3～6 hours, and yield can be accomplished the 8gL-prolineamide and single step reaction below raw material does not influence in the same old way.
Embodiment 4: a kind of preparation (2S)-N
The method of-chloracetyl-2-cyanic acid Pyrrolidine
Present embodiment is identical with the process of embodiment 1; Difference is: with prolyl chlorine in the step (2) be added drop-wise in the ammoniacal liquor temperature of reaction make-5 ℃～5 ℃ into; Reaction times made into 5～8 hours, and yield can be accomplished the 8gL-prolineamide and single step reaction below raw material does not influence in the same old way.
The above; Being merely preferred embodiment of the present invention, is not that the present invention is done any formal and substantial restriction, allly is familiar with the professional and technical personnel; In not breaking away from technical scheme scope of the present invention; The technology contents that is disclosed more than capable of using, and a little change of making, modify the equivalent variations with differentiation, be equivalent embodiment of the present invention; Simultaneously, all foundations essence technology of the present invention all still belongs in the scope of technical scheme of the present invention change, modification and the differentiation of any equivalent variations that above embodiment did.
Claims (10)
1. method for preparing (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine may further comprise the steps:
(1), L-proline(Pro) and sulfur oxychloride generation acylation reaction, obtain L-prolyl villaumite hydrochlorate, temperature of reaction is-10 ℃～110 ℃, the reaction times is 1～10 hour, reaction formula is following:
(2), L-prolyl chlorine and ammoniacal liquor reacts and generates the L-prolineamide, temperature of reaction is-10 ℃～40 ℃, the reaction times is 1～10 hour, reaction formula is following:
(3), L-prolineamide and chloroacetyl chloride react and obtain (2S)-N-chloracetyl-2-formamido-Pyrrolidine, temperature of reaction is 0 ℃～70 ℃, the reaction times is 1～10 hour, reaction formula is following:
(4), (2S)-N-chloracetyl-2-formamido-Pyrrolidine generates (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine with POCl3 generation dehydration reaction under coldcondition; Temperature of reaction is-15 ℃～30 ℃; Reaction times is 1～10 hour, and reaction formula is following:
2. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is characterized in that: the described solvent of step (1) is methylene dichloride, trichloromethane, toluene or benzene.
3. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is characterized in that: the mol ratio of L-proline(Pro) and sulfur oxychloride is 1 in the step (1): (1～4); Preferred L-proline(Pro) and sulfur oxychloride mol ratio are 1: 2.
4. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is characterized in that: step (2) described L-prolyl chlorine and ammoniacal liquor mol ratio are 1: (5～30); Preferred L-prolyl chlorine and ammoniacal liquor mol ratio are 1: 10.
5. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is characterized in that: the mol ratio of described L-prolineamide of step (3) and chloroacetyl chloride is 1: (1～2); The mol ratio of preferred L-prolineamide and chloroacetyl chloride is 1: 1.2.
6. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is characterized in that: the temperature of reaction of described L-prolineamide of step (3) and chloroacetyl chloride is 0 ℃～70 ℃, and the reaction times is 1～2 hour.
7. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is characterized in that: the temperature of reaction of described L-prolineamide of step (3) and chloroacetyl chloride is 10 ℃～70 ℃, and the reaction times is 1 hour.
8. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is characterized in that: the mol ratio of described (the 2S)-1-chloracetyl of step (4)-2-formamido-Pyrrolidine and POCl3 is 1: (1～5).
9. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine is characterized in that: the mol ratio of described (the 2S)-1-chloracetyl of step (4)-2-formamido-Pyrrolidine and POCl3 is 1: 2.
10. the method for a kind of preparation according to claim 1 (2S)-N-chloracetyl-2-cyanic acid Pyrrolidine; It is characterized in that: the temperature of reaction of described (the 2S)-1-chloracetyl of step (4)-2-formamido-Pyrrolidine and POCl3 is-5 ℃～30 ℃, and the reaction times is 1～8 hour.
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Cited By (7)
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| CN103787944A (en) * | 2012-11-01 | 2014-05-14 | 天津药物研究院 | Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine |
| CN103804266A (en) * | 2014-02-21 | 2014-05-21 | 张家港威胜生物医药有限公司 | Synthetic method of vildagliptin intermediate |
| CN103896819A (en) * | 2014-03-25 | 2014-07-02 | 宁波美诺华药业股份有限公司 | Preparation method of (S)-1-chloracetylpyrrolidine-2-formamide |
| WO2015092806A1 (en) * | 2013-12-18 | 2015-06-25 | Harman Finochem Limited | An advanced and cost-effective process for preparing highly pure vildagliptin |
| CN107501154A (en) * | 2017-09-13 | 2017-12-22 | 浙江普洛康裕制药有限公司 | (S) synthetic method of the formonitrile HCN of 1 (2 chloracetyl) pyrrolidines 2 |
| CN109111386A (en) * | 2018-09-03 | 2019-01-01 | 南京红杉生物科技有限公司 | The synthetic method of L- prolineamide |
| CN109827984A (en) * | 2019-02-27 | 2019-05-31 | 南京江北新区生物医药公共服务平台有限公司 | A method of measurement L- prolineamide synthesis technology impurity or its analogue reference substance content |
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| CN103787944A (en) * | 2012-11-01 | 2014-05-14 | 天津药物研究院 | Preparation method of 1-(2-chloroacetyl)-2-(S)-nitrile pyrrolidine |
| WO2015092806A1 (en) * | 2013-12-18 | 2015-06-25 | Harman Finochem Limited | An advanced and cost-effective process for preparing highly pure vildagliptin |
| CN103804266A (en) * | 2014-02-21 | 2014-05-21 | 张家港威胜生物医药有限公司 | Synthetic method of vildagliptin intermediate |
| CN103804266B (en) * | 2014-02-21 | 2016-06-08 | 张家港威胜生物医药有限公司 | A kind of synthetic method of vildagliptin intermediate |
| CN103896819A (en) * | 2014-03-25 | 2014-07-02 | 宁波美诺华药业股份有限公司 | Preparation method of (S)-1-chloracetylpyrrolidine-2-formamide |
| CN103896819B (en) * | 2014-03-25 | 2016-02-24 | 宁波美诺华药业股份有限公司 | A kind of preparation method of (S)-1-chloracetyl tetramethyleneimine-2-methane amide |
| CN107501154A (en) * | 2017-09-13 | 2017-12-22 | 浙江普洛康裕制药有限公司 | (S) synthetic method of the formonitrile HCN of 1 (2 chloracetyl) pyrrolidines 2 |
| CN109111386A (en) * | 2018-09-03 | 2019-01-01 | 南京红杉生物科技有限公司 | The synthetic method of L- prolineamide |
| CN109827984A (en) * | 2019-02-27 | 2019-05-31 | 南京江北新区生物医药公共服务平台有限公司 | A method of measurement L- prolineamide synthesis technology impurity or its analogue reference substance content |
| CN109827984B (en) * | 2019-02-27 | 2022-05-17 | 南京江北新区生物医药公共服务平台有限公司 | Method for determining content of impurities or structural analogue reference substances in L-prolinamide synthesis process |
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