CN101759619A - Preparation method of (S)-3-hydroxyl pyrrolidine and N-derivant thereof - Google Patents
Preparation method of (S)-3-hydroxyl pyrrolidine and N-derivant thereof Download PDFInfo
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- CN101759619A CN101759619A CN201010017975A CN201010017975A CN101759619A CN 101759619 A CN101759619 A CN 101759619A CN 201010017975 A CN201010017975 A CN 201010017975A CN 201010017975 A CN201010017975 A CN 201010017975A CN 101759619 A CN101759619 A CN 101759619A
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Abstract
The invention provides a preparation method of (S)-3-hydroxyl pyrrolidine and an N-derivant thereof, comprising the following synthesizing steps of: firstly performing reaction of L-malic acid as a raw material with amine (or ammonia) to generate acid amide; and then carrying out closed ring of the acid amide to generate diimide; reducing, and the like to obtain a target product. Compared with other synthesizing routes, the invention has the advantages of shorter route, higher yield coefficient, lower cost, safety, environmental protection, simple operation, and the like.
Description
Technical field
The present invention relates to the preparation method of a kind of (S)-3-hydroxyl pyrrolidine and N-derivative thereof.
Background technology
(S)-the 3-hydroxyl pyrrolidine is synthetic darifenacin (Darifenacin) important intermediate, darifenacin is used for the treatment of bladder hyperactivity hyperkinesia diseases (OAB) such as the urinary incontinence, urgent urination and frequent micturition, its M3 acts in all OAB medicines has uniqueness, make the incidence that slow releasing tablet can reduce nervus centralis and cardiovascular adverse effects, the darifenacin slow releasing tablet is very useful with new concept treatment bladder hyperactivity hyperkinesia disease.
Document (Tetrahedron Letters, 1991,32 (3), 401-404; Tetrahedron, 1992,48 (16), 3313-3322; Journal of Medicinal Chemistry, 1994,37 (14), 2138-2144; Heterocycles, 1996,43 (2); 41 5-423) reported (S)-3-acetoxyl group-2; a kind of synthetic method of 5-dicarbapentaborane-N-benzyl-pyrrole alkane is that raw material is protected hydroxyl and made L MALIC ACID become intramolecular acid anhydride with excess acetyl chloride with the L MALIC ACID, again with benzylamine Cheng Huan.Reaction scheme length, complex process, total recovery are low, can not satisfy industrialization demands.
Document (CN101289445; Journal of Molecular Catalysis A:Chemical, 2006,250 (1-2), 104-113; ) reported a kind of synthetic method of (S)-3-hydroxy-n-benzyl-pyrrole alkane, with LiAlH
4Be reductive agent, make that reduction reaction technology is dangerous and be difficult to industrialization.
Summary of the invention
The objective of the invention is to overcome the deficiency that prior art exists, the preparation method of a kind of (S)-3-hydroxyl pyrrolidine and N-derivative thereof is provided.
Purpose of the present invention is achieved through the following technical solutions:
(S)-and the preparation method of 3-hydroxyl pyrrolidine and N-derivative thereof, described (S)-3-hydroxyl pyrrolidine and N-derivative thereof have structure shown in the formula (1):
It is characterized in that: may further comprise the steps:
1. starting raw material L MALIC ACID and amine or ammonia are reacted into acid amides in 55～150 ℃ in solvent, obtain the intermediate of structure shown in the formula (2):
The mol ratio of amine or ammonia and L MALIC ACID is 0.6: 1～1.5: 1;
2. the acid amides that step is obtained in 1. becomes di carbonyl imide in 80～250 ℃ of closed loops in solvent, obtains intermediate 3, and structure is depicted as formula (3):
3. the intermediate 3 that step is obtained in 2. is in solvent, under the condition that acid or acyl chlorides exist with metal borohydride in-30～70 ℃ of reactions; Or with red aluminium in 50～150 ℃ of reactions,
Obtain (S)-3-hydroxy-n-substituted pyrrolidin 1 of structure shown in the formula (1):
4. the intermediate 4 that is benzyl with the 3. middle R of step in 0.2～5MPa, 45～100 ℃ of hydrogenations under catalyzer, obtains (S)-3-hydroxyl pyrrolidine 1a in solvent, and structure is depicted as formula (1a):
Further, above-mentioned (the S)-3-hydroxyl pyrrolidine and the preparation method of N-derivative thereof is characterized in that: the R in the formula (1) be H ,-CH
3,-CH
2CH
3,-CH
2COOCH
3,-CH
2CONH
2Or-CH
2Ph.
Further, above-mentioned (the S)-3-hydroxyl pyrrolidine and the preparation method of N-derivative thereof, step 1. in, described ammonia is meant ammonia or ammoniacal liquor, amine is meant methylamine, ethamine, glycine methyl ester or benzylamine, and solvent is meant one or more the mixture in methyl alcohol, ethanol, propyl alcohol, the water.
Further, above-mentioned (the S)-3-hydroxyl pyrrolidine and the preparation method of N-derivative thereof, step 2. in, described solvent is one or more the mixture in toluene, dimethylbenzene, toluene dichloride, chloroform, the ethylene dichloride.
Further, above-mentioned (the S)-3-hydroxyl pyrrolidine and the preparation method of N-derivative thereof, step 3. in, described acid is LiCl, AlCl
3, I
2, sulfuric acid, acetate, boron trifluoride or trifluoroacetic acid, acyl chlorides is sulfur oxychloride, phosphorus oxychloride or methyl sulfur oxychloride, described metal hydroborates is sodium borohydride or POTASSIUM BOROHYDRIDE, described red aluminium is [NaAl (OCH
2CH
2OCH
3)
2] H
2With the mixed solution of toluene, described solvent is one or more the mixture in ethers, alcohols, methylene dichloride, chloroform, ethylene dichloride, the water.Described ethers is ether, t-butyl methyl ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran.Described alcohols is methyl alcohol, ethanol or the trimethyl carbinol.
Again further, above-mentioned (the S)-3-hydroxyl pyrrolidine and the preparation method of N-derivative thereof, step 4. in, described catalyzer is palladium charcoal or Raney's nickel, described solvent is one or both the mixture in alcohols, the water.Described alcohols is methyl alcohol, ethanol or the trimethyl carbinol.
Substantive distinguishing features and obvious improvement that technical solution of the present invention is outstanding are mainly reflected in:
1. cheap, the environmental protection of cost of material used in the present invention, conventional production unit can be produced;
2. the present invention compared with prior art, it has, and route is shorter, yield is higher, cost is lower, safety and environmental protection, simple operation and other advantages, and suitability for industrialized production.
Description of drawings
Below in conjunction with accompanying drawing technical solution of the present invention is described further:
Fig. 1: reaction equation of the present invention.
Embodiment
The invention provides the preparation method of a kind of (S)-3-hydroxyl pyrrolidine and N-derivative thereof, it has, and route is shorter, yield is higher, cost is lower, safety and environmental protection, simple operation and other advantages, and suitable suitability for industrialized production.
As shown in Figure 1, (S)-preparation method of 3-hydroxyl pyrrolidine and N-derivative thereof, described (S)-3-hydroxyl pyrrolidine and N-derivative thereof have structure shown in the formula (1):
With the L MALIC ACID is raw material, becomes acid amides with amine (or ammonia) earlier, and closed loop becomes synthesis steps such as imide, reduction again, finally obtains target product, specifically may further comprise the steps:
1. starting raw material L MALIC ACID and amine or ammonia are reacted into acid amides in 55～150 ℃ in solvent, obtain the intermediate of structure shown in the formula (2):
The mol ratio of amine or ammonia and L MALIC ACID is 0.6: 1～1.5: 1;
2. the acid amides that step is obtained in 1. becomes di carbonyl imide in 80～250 ℃ of closed loops in solvent, obtains intermediate 3, and structure is depicted as formula (3):
3. the intermediate 3 that step is obtained in 2. is in solvent, under the condition that acid or acyl chlorides exist with metal borohydride in-30～70 ℃ of reactions; Or with red aluminium in 50～150 ℃ of reactions,
Obtain (S)-3-hydroxy-n-substituted pyrrolidin 1 of structure shown in the formula (1):
4. the intermediate 4 that is benzyl with the 3. middle R of step in 0.2～5MPa, 45～100 ℃ of hydrogenations under catalyzer, obtains (S)-3-hydroxyl pyrrolidine 1a in solvent, and structure is depicted as formula (1a):
Wherein, the R in the formula (1) be H ,-CH
3,-CH
2CH
3,-CH
2COOCH
3,-CH
2CONH
2Or-CH
2Ph.
Step 2. in, described solvent is one or more the mixture in toluene, dimethylbenzene, toluene dichloride, chloroform, the ethylene dichloride.
Step 4. in, described catalyzer is palladium charcoal or Raney's nickel, described solvent is one or both the mixture in alcohols, the water.Described alcohols is methyl alcohol, ethanol or the trimethyl carbinol.
Embodiment 1:3-hydroxy-n-benzyl-2,5-di carbonyl imide 3 synthetic
(116.0g 0.865mol) is dissolved among the methyl alcohol 200mL, is warming up to backflow, and (92.0g, 0.859mol) and the mixing solutions of methyl alcohol (50mL), reaction finishes the methyl alcohol of underpressure distillation afterwards, obtains flaxen oily matter to drip benzylamine with L MALIC ACID.Add toluene 250mL, be warming up to the backflow azeotropic water removing.Reaction finishes back cooling crystallization, gets white solid 155.2g, 99～101.5 ℃ of fusing points, yield 86.3%.Results of elemental analyses: (theoretical value: C=64.38%; H=5.40%; N=6.83%; O=23.39%; Detected value: C=65.51%; H=5.64%; N=6.59%; O=22.26%.)
Synthesizing of embodiment 2:3-hydroxy-n-benzyl-pyrrole alkane 1
(422g 1.461mol) is dissolved in the toluene (100mL), and nitrogen protection drips 3-hydroxy-n-benzyl-2, and (100g, toluene 0.487mol) (50mL) solution is warming up to backflow to the 5-di carbonyl imide with red aluminum solutions.Reaction finishes to dropwise at-10～25 ℃ of dropping sodium aqueous solution, adds chloroform 400mL.Layering, water layer merges organic layer with chloroform 500mL * 2 extractions, saturated aqueous common salt 100mL washing.The organic layer concentrating under reduced pressure gets faint yellow oily thing 76.5g, yield 87.4%.Results of elemental analyses: (theoretical value: C=74.54%; H=8.53%; N=7.90%; O=9.03%; Detected value: C=75.49%; H=8.54%; N=7.43%; O=8.54%.)
Embodiment 3:3-hydroxyl pyrrolidine 1a's is synthetic
(190g 1.072mol) is dissolved among the methyl alcohol 1200mL, adds 10% palladium charcoal 9g with 3-hydroxy-n-benzyl-pyrrole alkane, glacial acetic acid 63mL, in 55 ℃ of thermotonuses of 0.2MPa pressure, reaction finishes, and adds potassium hydroxide solution, underpressure distillation, add methylene dichloride 500mL, filter, underpressure distillation gets faint yellow oily thing 76.5g, yield 98.2%, e.e.99.66%.Results of elemental analyses: (theoretical value: C=55.15%; H=10.41%; N=16.08%; O=18.36%; Detected value: C=56.10%; H=10.32%; N=15.65%; O=17.93%.)
The foregoing description only is more detailed explanation the present invention, and scope of the present invention not only is confined to this.
The present invention compared with prior art, its employed cost of material is cheap, step reduces, overall yield is higher, and is simple to operate, has suitability for industrialized production and is worth.
What need understand is: the above only is a preferred implementation of the present invention; for those skilled in the art; under the prerequisite that does not break away from the principle of the invention, can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (9)
1. the preparation method of (S)-3-hydroxyl pyrrolidine and N-derivative thereof, described (S)-3-hydroxyl pyrrolidine and N-derivative thereof have structure shown in the formula (1):
It is characterized in that: may further comprise the steps:
1. starting raw material L MALIC ACID and amine or ammonia are reacted into acid amides in 55～150 ℃ in solvent, obtain the intermediate of structure shown in the formula (2):
The mol ratio of amine or ammonia and L MALIC ACID is 0.6: 1～1.5: 1;
2. the acid amides that step is obtained in 1. becomes di carbonyl imide in 80～250 ℃ of closed loops in solvent, obtains intermediate 3, and structure is depicted as formula (3):
3. the intermediate 3 that step is obtained in 2. is in solvent, under the condition that acid or acyl chlorides exist with metal borohydride in-30～70 ℃ of reactions; Or with red aluminium in 50～150 ℃ of reactions, obtain (S)-3-hydroxy-n-substituted pyrrolidin 1 of structure shown in the formula (1):
4. the intermediate 4 that is benzyl with the 3. middle R of step in 0.2～5MPa, 45～100 ℃ of hydrogenations under catalyzer, obtains (S)-3-hydroxyl pyrrolidine 1a in solvent, and structure is depicted as formula (1a):
2. the preparation method of (S)-3-hydroxyl pyrrolidine according to claim 1 and N-derivative thereof is characterized in that: the R in the formula (1) be H ,-CH
3,-CH
2CH
3,-CH
2COOCH
3,-CH
2CONH
2Or-CH
2Ph.
3. the preparation method of (S)-3-hydroxyl pyrrolidine according to claim 1 and N-derivative thereof, it is characterized in that: step 1. in, described ammonia is meant ammonia or ammoniacal liquor, amine is meant methylamine, ethamine, glycine methyl ester or benzylamine, and solvent is meant one or more the mixture in methyl alcohol, ethanol, propyl alcohol, the water.
4. the preparation method of (S)-3-hydroxyl pyrrolidine according to claim 1 and N-derivative thereof is characterized in that: step 2. in, described solvent is one or more the mixture in toluene, dimethylbenzene, toluene dichloride, chloroform, the ethylene dichloride.
5. the preparation method of (S)-3-hydroxyl pyrrolidine according to claim 1 and N-derivative thereof is characterized in that: step 3. in, described acid is LiCl, AlCl
3, I
2, sulfuric acid, acetate, boron trifluoride or trifluoroacetic acid, acyl chlorides is sulfur oxychloride, phosphorus oxychloride or methyl sulfur oxychloride, described metal hydroborates is sodium borohydride or POTASSIUM BOROHYDRIDE, described red aluminium is [NaAl (OCH
2CH
2OCH
3)
2] H
2With the mixed solution of toluene, described solvent is one or more the mixture in ethers, alcohols, methylene dichloride, chloroform, ethylene dichloride, the water.
6. the preparation method of (S)-3-hydroxyl pyrrolidine according to claim 5 and N-derivative thereof is characterized in that: described ethers is ether, t-butyl methyl ether, tetrahydrofuran (THF) or 2-methyltetrahydrofuran.
7. the preparation method of (S)-3-hydroxyl pyrrolidine according to claim 5 and N-derivative thereof is characterized in that: described alcohols is methyl alcohol, ethanol or the trimethyl carbinol.
8. the preparation method of (S)-3-hydroxyl pyrrolidine according to claim 1 and N-derivative thereof is characterized in that: step 4. in, described catalyzer is palladium charcoal or Raney's nickel, described solvent is one or both the mixture in alcohols, the water.
9. the preparation method of (S)-3-hydroxyl pyrrolidine according to claim 8 and N-derivative thereof is characterized in that: described alcohols is methyl alcohol, ethanol or the trimethyl carbinol.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012231A (en) * | 2012-12-14 | 2013-04-03 | 沈阳药科大学 | Preparation method and application of glycopyrronium bromide chiral antipode |
| JP2019524752A (en) * | 2016-08-02 | 2019-09-05 | ダーミラ， インク．Ｄｅｒｍｉｒａ， Ｉｎｃ． | Methods for making and using glycopyrronium compounds |
| CN111518007A (en) * | 2020-04-30 | 2020-08-11 | 安徽德信佳生物医药有限公司 | Synthesis method of (S) -3-pyrrolidinol hydrochloride |
| CN113307757A (en) * | 2021-05-26 | 2021-08-27 | 南京德克瑞医药化工有限公司 | Preparation method of medical intermediate N-benzyl-3-pyrroline |
-
2010
- 2010-01-19 CN CN201010017975A patent/CN101759619A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| KRISHNA L. BHAT等: "SYNTHETIC ROUTES TO CHIRAL 3-PYRROLINDINOLS", 《SYNTHETIC COMMUNICATIONS》 * |
| PETR KOCALKA等: "Synthesis of racemic and enantiomeric 3-pyrrolidinyl derivatives of nucleobases", 《TETRAHEDRON》 * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103012231A (en) * | 2012-12-14 | 2013-04-03 | 沈阳药科大学 | Preparation method and application of glycopyrronium bromide chiral antipode |
| CN103012231B (en) * | 2012-12-14 | 2015-08-05 | 沈阳药科大学 | The preparation method and application of Glycopyrronium Bromide chiral enantiomer |
| JP2019524752A (en) * | 2016-08-02 | 2019-09-05 | ダーミラ， インク．Ｄｅｒｍｉｒａ， Ｉｎｃ． | Methods for making and using glycopyrronium compounds |
| US11352323B2 (en) | 2016-08-02 | 2022-06-07 | Journey Medical Corporation | Processes for making, and methods of using, glycopyrronium compounds |
| JP7161466B2 (en) | 2016-08-02 | 2022-10-26 | ジャーニー メディカル コーポレーション | Methods for making and using glycopyrronium compounds |
| CN111518007A (en) * | 2020-04-30 | 2020-08-11 | 安徽德信佳生物医药有限公司 | Synthesis method of (S) -3-pyrrolidinol hydrochloride |
| CN113307757A (en) * | 2021-05-26 | 2021-08-27 | 南京德克瑞医药化工有限公司 | Preparation method of medical intermediate N-benzyl-3-pyrroline |
| CN113307757B (en) * | 2021-05-26 | 2022-04-29 | 南京德克瑞医药化工有限公司 | Preparation method of medical intermediate N-benzyl-3-pyrroline |
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Application publication date: 20100630 |