CN114230503A - Method for synthesizing vildagliptin by one-pot method - Google Patents
Method for synthesizing vildagliptin by one-pot method Download PDFInfo
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- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 46
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 46
- 238000000034 method Methods 0.000 title claims abstract description 22
- 238000005580 one pot reaction Methods 0.000 title claims abstract description 17
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 7
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 claims abstract description 17
- DWPIPTNBOVJYAD-BQKDNTBBSA-N (5s,7r)-3-aminoadamantan-1-ol Chemical compound C([C@H](C1)C2)[C@@H]3CC2(N)CC1(O)C3 DWPIPTNBOVJYAD-BQKDNTBBSA-N 0.000 claims abstract description 13
- 239000012024 dehydrating agents Substances 0.000 claims abstract description 13
- QABLOFMHHSOFRJ-UHFFFAOYSA-N methyl 2-chloroacetate Chemical compound COC(=O)CCl QABLOFMHHSOFRJ-UHFFFAOYSA-N 0.000 claims abstract description 12
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 11
- 239000003054 catalyst Substances 0.000 claims abstract description 9
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 6
- 238000005917 acylation reaction Methods 0.000 claims abstract description 5
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 26
- 239000012074 organic phase Substances 0.000 claims description 21
- 239000000047 product Substances 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 15
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 12
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 12
- 238000003756 stirring Methods 0.000 claims description 11
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 10
- 238000001308 synthesis method Methods 0.000 claims description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 8
- 238000006297 dehydration reaction Methods 0.000 claims description 7
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012071 phase Substances 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 239000007787 solid Substances 0.000 claims description 5
- YSHOWEKUVWPFNR-UHFFFAOYSA-N burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 claims description 4
- MGNCLNQXLYJVJD-UHFFFAOYSA-N cyanuric chloride Chemical compound ClC1=NC(Cl)=NC(Cl)=N1 MGNCLNQXLYJVJD-UHFFFAOYSA-N 0.000 claims description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 claims description 4
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- 238000010791 quenching Methods 0.000 claims description 3
- YCWRPKBYQZOLCD-LURJTMIESA-N (2s)-1-(2-chloroacetyl)pyrrolidine-2-carbonitrile Chemical compound ClCC(=O)N1CCC[C@H]1C#N YCWRPKBYQZOLCD-LURJTMIESA-N 0.000 claims description 2
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 claims description 2
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims 1
- 230000000717 retained effect Effects 0.000 claims 1
- 239000002253 acid Substances 0.000 abstract description 4
- 239000011230 binding agent Substances 0.000 abstract description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- ZQBVUULQVWCGDQ-UHFFFAOYSA-N propan-1-ol;propan-2-ol Chemical compound CCCO.CC(C)O ZQBVUULQVWCGDQ-UHFFFAOYSA-N 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000126 substance Substances 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
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- CJJMAWPEZKYJAP-UHFFFAOYSA-N 3-hydroxyadamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2(O)CC1(C(=O)O)C3 CJJMAWPEZKYJAP-UHFFFAOYSA-N 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 description 1
- 108010088406 Glucagon-Like Peptides Proteins 0.000 description 1
- 102400000322 Glucagon-like peptide 1 Human genes 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- UIUXUFNYAYAMOE-UHFFFAOYSA-N methylsilane Chemical compound [SiH3]C UIUXUFNYAYAMOE-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- ALSCEGDXFJIYES-UHFFFAOYSA-N pyrrolidine-2-carbonitrile Chemical compound N#CC1CCCN1 ALSCEGDXFJIYES-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a method for synthesizing vildagliptin by a one-pot method. Carrying out acylation reaction on L-prolinamide and methyl chloroacetate under the action of a catalyst to obtain an intermediate 1; treating the intermediate 1 with a dehydrating agent to obtain an intermediate 2; and carrying out two-phase reaction on the intermediate 2 and 3-amino-1-adamantanol under the action of a phase transfer catalyst and an inorganic base to obtain vildagliptin. The method greatly reduces the process flow, avoids the use of acid binding agent, omits the post-treatment process of intermediate, improves the overall yield and reduces the cost.
Description
Technical Field
The invention relates to a method for synthesizing vildagliptin by a one-pot method, and belongs to the technical field of medicines.
Background
Vildagliptin (vildagliptin) is a dipeptidyl peptidase-4 (DPP-4) inhibitor originally developed by nova pharmaceuticals, inc. Vildagliptin can selectively stimulate glucagon-like polypeptide 1(GLP-1), plays a role in promoting insulin secretion, and is not easy to cause hypoglycemia, so that vildagliptin is a medicine with good application prospect. The current vildagliptin market demand is continuously rising, the industry development prospect is good, and the market scale is about $ 15 billion.
Vildagliptin, chemical formula is: (-) - (2S) -1- [ [ (3-Hydroxytricyclo [3.3.1.1[3,7 ]]]Silane-1-yl) amino]Acetyl group]Pyrrolidine-2-carbonitrile, molecular formula: c17H25N3O2The structural formula:
WO0034241A1 of Nowa company reports a synthesis method of vildagliptin, which takes prolinamide as a starting material, prepares an intermediate through chloroacetylation (using an acid-binding agent such as potassium carbonate) and trifluoroacetic anhydride dehydration, and finally reacts with 3-amino-1-adamantanol at normal temperature for 6 days to prepare vildagliptin, wherein the yield and the product purity of the reaction are lower.
CN201911059103.4 discloses a preparation method of vildagliptin, which adopts methylsilane to protect amino on 3-amino-1-adamantanol, reduces side reaction and improves yield, but has the defect of complex operation.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a one-pot method for synthesizing vildagliptin, wherein L-prolinamide and methyl chloroacetate are subjected to acylation reaction under the action of a catalyst to obtain an intermediate 1; treating the intermediate 1 with a dehydrating agent to obtain an intermediate 2; and carrying out two-phase reaction on the intermediate 2 and the 3-amino-1-adamantanol under the action of a phase transfer catalyst and an inorganic base to obtain a product. The method greatly reduces the process flow, avoids the use of acid binding agent, omits the post-treatment process of intermediate, improves the overall yield and reduces the cost.
The purpose of the invention is realized by the following technical scheme: the method for synthesizing vildagliptin by a one-pot method is characterized in that L-prolinamide and methyl chloroacetate are subjected to acylation reaction under the action of a catalyst to obtain an intermediate 1((2S) -N-chloroacetyl-2-formamido tetrahydropyrrole); treating the intermediate 1 by a dehydrating agent to obtain an intermediate 2((2S) -N-chloroacetyl-2-cyano tetrahydropyrrole); the intermediate 2 and 3-amino-1-adamantanol are subjected to two-phase reaction under the action of a phase transfer catalyst and an inorganic base to obtain a product, and the synthetic route is shown as follows.
The method specifically comprises the following steps:
1) 1, 2-dichloroethane is used as a solvent, and L-prolinamide and methyl chloroacetate are subjected to reflux reaction with a catalyst to obtain an intermediate 1;
2) directly adding a dehydrating agent into the intermediate 1 without treatment, performing dehydration reaction to obtain an intermediate 2, adding water to quench the dehydrating agent after the reaction is finished, standing for layering, and keeping an organic phase;
3) adding water, potassium carbonate, 3-amino-1-adamantanol and a phase transfer catalyst into the organic phase obtained in the step 2) to carry out two-phase reaction, so as to synthesize vildagliptin.
Further, filtering the reaction liquid obtained in the step 3), standing for layering, keeping an organic phase, evaporating 1, 2-dichloroethane to dryness until the 1, 2-dichloroethane is oily, adding methyl tert-butyl ether, stirring at low temperature to separate out a white-like solid, filtering, and recrystallizing a filter cake with an isopropanol methyl tert-butyl ether mixed solvent to obtain a crude vildagliptin product.
Further, recrystallizing the crude vildagliptin product with butanone to obtain a fine vildagliptin product.
Wherein the content of the first and second substances,
in the step 1), the catalyst is one or a mixture of more of DMAP (4-dimethylaminopyridine), HOBT (1-hydroxybenzotriazole) and 4-PPY (4-pyrrolidinylpyridine), and DMAP is preferred.
In the step 1), the molar ratio of the L-prolinamide to the methyl chloroacetate to the catalyst is 1:1-1.2:0.025-0.1, preferably 1:1.05: 0.05.
In the step 1), the mass ratio of the L-prolinamide to the 1, 2-dichloroethane is 1:8-20, preferably 1: 15.
In the step 1), the reflux reaction is carried out for 5 to 8 hours.
In the step 2), the dehydrating agent is one or a mixture of more of cyanuric chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus pentoxide, phosphorus oxychloride and Burgess reagent, and cyanuric chloride is preferred.
In the step 2), the molar ratio of the L-prolinamide to the dehydrating agent is 1:1-3, preferably 1: 1.5.
In the step 2), the dehydration reaction temperature is 40-50 ℃, the reaction time is 2-12h, and the reaction is preferably carried out for 8h at 40 ℃.
In the step 3), the phase transfer catalyst is one or a mixture of any more of benzyltriethylammonium chloride, tetrabutylammonium bromide, PEG-500 and 18 crown 6, and tetrabutylammonium chloride is preferred.
In the step 3), the molar ratio of L-prolinamide to potassium carbonate to 3-amino-1-adamantanol is 1:1.1-4:1-1.5, preferably 1:2: 1.1.
In the step 3), the mass ratio of the L-prolinamide to the water to the phase transfer catalyst is 1:3-8:0.005-0.05, preferably 1:3.75: 0.025-0.05.
In the step 3), the reaction temperature is 30-50 ℃, the reaction time is 4-18 h, and the reaction is preferably carried out at 40 ℃ for 12 h.
The invention has the advantages that:
1. methyl chloroacetate is used as a reaction raw material, so that an acid-binding agent is avoided in the acylation reaction, and the yield is improved;
2. after the reaction of L-prolinamide and methyl chloroacetate, a dehydrating agent can be directly added without treatment for dehydration reaction to generate an intermediate 1, after dehydration, feed liquid only needs to be added with water to quench the dehydrating agent, and then the water layer is layered and discarded; adding 3-amino-1-adamantanol, potassium carbonate, water and a phase transfer catalyst into the residual organic phase without treatment to perform two-phase reaction to directly obtain vildagliptin;
3. and the final feed liquid after the vildagliptin is generated is alkaline, the water layer has large salt content, the product is enriched in an organic phase, and the product is obtained by crystallizing after the organic phase is evaporated to dryness.
The invention adopts a one-pot method, greatly simplifies the operation steps, omits the post-treatment process of an intermediate, improves the overall yield and reduces the cost.
Detailed Description
The present invention is further described below by way of specific examples, but the present invention is not limited to only the following examples. The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.
Example 1:
600g of 1, 2-dichloroethane was added to a 1L three-necked flask, stirring was started, 40g L-prolinamide, 40.0g of methyl chloroacetate, and 2.1g of DMAP were added, and the mixture was heated to reflux and reacted for 6 hours. The temperature is reduced to 40 ℃, 97.0g of cyanuric chloride is added, and the reaction is continued for 8 hours.
The reaction is cooled to 30 ℃, 150mL of water is added, the mixture is stirred for 1 hour, and the mixture is kept stand for layering, and an organic phase is remained. The organic phase was transferred back to the 1L reaction flask again, stirring was turned on, and then 150mL of water, 1g of tetrabutylammonium chloride, 96.9g of anhydrous potassium carbonate powder, 64.5g of 3-amino-1-adamantanol were added and reacted at 40 ℃ for 12 hours.
The reaction liquid is filtered, kept stand for layering, and an organic phase is reserved. The organic phase was washed with 100mL of water and the layers were separated. Evaporating 1, 2-dichloroethane to dryness to obtain oil, adding 450mL methyl tert-butyl ether, stirring at 10 deg.C to precipitate off white solid, filtering, and adding 400mL isopropanol methyl tert-butyl ether mixed solvent (mIsopropanol (I-propanol):mMethyl tert-butyl etherAnd (5: 1) recrystallizing to obtain a crude vildagliptin product. Recrystallizing the crude vildagliptin product with 400mL butanone to obtain a fine vildagliptin product, and drying to obtain 52.7g with the yield of 49.6%.
Example 2:
600g of 1, 2-dichloroethane was added to a 1L three-necked flask, stirring was started, 40g L-prolinamide, 40.0g of methyl chloroacetate, and 2.1g of DMAP were added, and the mixture was heated to reflux and reacted for 6 hours. The temperature is reduced to 40 ℃, 72.1g of phosphorus trichloride is added, and the reaction is continued for 8 hours.
The reaction is cooled to 30 ℃, 150mL of water is added, the mixture is stirred for 1 hour, and the mixture is kept stand for layering, and an organic phase is remained. The organic phase was transferred back to the 1L reaction flask again, stirring was turned on, and then 150mL of water, 1.5g of benzyltriethylammonium chloride, 96.9g of anhydrous potassium carbonate powder, 64.5g of 3-amino-1-adamantanol were added and reacted at 40 ℃ for 12 hours.
The reaction liquid is filtered, kept stand for layering, and an organic phase is reserved. The organic phase was washed with 100mL of water and the layers were separated. Evaporating 1, 2-dichloroethane to dryness to obtain oil, adding 450mL methyl tert-butyl ether, stirring at 10 deg.C to precipitate off white solid, filtering, and adding 400mL isopropanol methyl tert-butyl ether mixed solvent (mIsopropanol (I-propanol):mMethyl tert-butyl etherAnd (5: 1) recrystallizing to obtain a crude vildagliptin product. Recrystallizing the crude vildagliptin product with 400mL butanone to obtain a fine vildagliptin product, and drying to obtain 56.0g, wherein the yield is 52.7%.
Example 3:
600g of 1, 2-dichloroethane was added to a 1L three-necked flask, stirring was started, and 40g L-prolinamide, 40.0g of methyl chloroacetate, and 2.6g of 4-PPY were added thereto, and the mixture was heated to reflux and reacted for 6 hours. The temperature is reduced to 40 ℃, 83.0g of phosphorus pentachloride is added in two batches with 20min interval, and the reaction is continued for 8 h.
The reaction is cooled to 30 ℃, 150mL of water is added, the mixture is stirred for 1 hour, and the mixture is kept stand for layering, and an organic phase is remained. The organic phase was transferred back to the 1L reaction flask, stirring was turned on, and then 150mL of water, 2.0g of PEG-500, 96.9g of anhydrous potassium carbonate powder, 64.5g of 3-amino-1-adamantanol, and reacted at 40 ℃ for 16 hours.
The reaction liquid is filtered, kept stand for layering, and an organic phase is reserved. The organic phase was washed with 100mL of water and the layers were separated. Evaporating 1, 2-dichloroethane to dryness to obtain oil, adding 450mL methyl tert-butyl ether, stirring at 10 deg.C to precipitate off white solid, filtering, and adding 400mL isopropanol methyl tert-butyl ether mixed solvent (mIsopropanol (I-propanol):mMethyl tert-butyl etherAnd (5: 1) recrystallizing to obtain a crude vildagliptin product. Recrystallizing the crude vildagliptin product with 400mL butanone to obtain a fine vildagliptin product, and drying to obtain 57.4g with a yield of 54.1%.
Claims (10)
1. The method for synthesizing vildagliptin by a one-pot method is characterized in that L-prolinamide and methyl chloroacetate are subjected to acylation reaction under the action of a catalyst to obtain an intermediate 1; treating the intermediate 1 with a dehydrating agent to obtain an intermediate 2; carrying out two-phase reaction on the intermediate 2 and 3-amino-1-adamantanol under the action of a phase transfer catalyst and an inorganic base to obtain vildagliptin;
the intermediate 1 is (2S) -N-chloracetyl-2-formamido tetrahydropyrrole; intermediate 2 is (2S) -N-chloroacetyl-2-cyanotetrahydropyrrole.
2. The one-pot vildagliptin synthesis method according to claim 1, comprising the steps of:
1) 1, 2-dichloroethane is used as a solvent, and L-prolinamide and methyl chloroacetate are subjected to reflux reaction with a catalyst to obtain an intermediate 1; the catalyst is one or a mixture of more of 4-dimethylamino pyridine, 1-hydroxybenzotriazole and 4-pyrrolidinyl pyridine;
2) directly adding a dehydrating agent into the intermediate 1 without treatment, performing dehydration reaction to obtain an intermediate 2, adding water to quench the dehydrating agent after the reaction is finished, standing for layering, and keeping an organic phase;
3) adding water, inorganic base, 3-amino-1-adamantanol and a phase transfer catalyst into the organic phase obtained in the step 2) to carry out two-phase reaction to synthesize vildagliptin.
3. The one-pot vildagliptin synthesis method as claimed in claim 2, wherein the reaction solution in step 3) is filtered, kept standing for layering, an organic phase is retained, 1, 2-dichloroethane is evaporated to be oily, methyl tert-butyl ether is added, low-temperature stirring is carried out to separate out a white-like solid, filtering is carried out, and a filter cake is recrystallized by using an isopropanol methyl tert-butyl ether mixed solvent to obtain a crude vildagliptin product.
4. The one-pot vildagliptin synthesis method as claimed in claim 3, wherein the vildagliptin crude product is recrystallized with butanone to obtain vildagliptin refined product.
5. The one-pot vildagliptin synthesis method according to any one of claims 1-4, wherein the dehydrating agent is one or a mixture of any more of cyanuric chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus pentoxide, phosphorus oxychloride and Burgess reagent.
6. The one-pot vildagliptin synthesis method according to any one of claims 1 to 4, wherein the dehydration reaction temperature in step 2) is 40-50 ℃, and the reaction time is 2-12 h.
7. The one-pot vildagliptin synthesis method according to any one of claims 1-4, wherein the phase transfer catalyst is one or a mixture of any of benzyltriethylammonium chloride, tetrabutylammonium bromide, PEG-500 and 18 crown 6.
8. The one-pot vildagliptin synthesis method according to any one of claims 1 to 4, wherein in the step 3), the reaction temperature is 30-50 ℃, and the reaction time is 4-18 h.
9. The one-pot vildagliptin synthesis method according to any one of claims 1 to 4, wherein in step 3), the inorganic base is potassium carbonate.
10. The one-pot vildagliptin synthesis method according to any one of claims 1 to 4, wherein the mass ratio of L-prolinamide, water and phase transfer catalyst is 1:3-8: 0.005-0.05.
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