CN100588646C - Industrial preparation method for 3-amino-2, 2-dimethyl propionamide - Google Patents
Industrial preparation method for 3-amino-2, 2-dimethyl propionamide Download PDFInfo
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- CN100588646C CN100588646C CN200510112039A CN200510112039A CN100588646C CN 100588646 C CN100588646 C CN 100588646C CN 200510112039 A CN200510112039 A CN 200510112039A CN 200510112039 A CN200510112039 A CN 200510112039A CN 100588646 C CN100588646 C CN 100588646C
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- 238000002360 preparation method Methods 0.000 title description 7
- HKQZJXVIXAPOPZ-UHFFFAOYSA-N 3-amino-2,2-dimethylpropanamide Chemical compound NCC(C)(C)C(N)=O HKQZJXVIXAPOPZ-UHFFFAOYSA-N 0.000 title 1
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 238000000034 method Methods 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 238000004519 manufacturing process Methods 0.000 claims abstract description 7
- 239000002994 raw material Substances 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- QJQAMHYHNCADNR-UHFFFAOYSA-N n-methylpropanamide Chemical compound CCC(=O)NC QJQAMHYHNCADNR-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- 229910000085 borane Inorganic materials 0.000 claims description 8
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 8
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 7
- 239000012298 atmosphere Substances 0.000 claims description 7
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 claims description 6
- 238000005984 hydrogenation reaction Methods 0.000 claims description 6
- 230000002829 reductive effect Effects 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- 238000006722 reduction reaction Methods 0.000 claims description 5
- 238000004904 shortening Methods 0.000 claims description 5
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 claims description 4
- 230000029936 alkylation Effects 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- 239000012280 lithium aluminium hydride Substances 0.000 claims description 3
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 3
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 2
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 2
- 230000001035 methylating effect Effects 0.000 claims description 2
- 239000000758 substrate Substances 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims 2
- 238000000746 purification Methods 0.000 abstract description 5
- 238000004440 column chromatography Methods 0.000 abstract description 4
- 239000003112 inhibitor Substances 0.000 abstract description 4
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 abstract description 4
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- 229940080818 propionamide Drugs 0.000 abstract 2
- 102000010911 Enzyme Precursors Human genes 0.000 abstract 1
- 108010062466 Enzyme Precursors Proteins 0.000 abstract 1
- 230000003197 catalytic effect Effects 0.000 abstract 1
- 231100000331 toxic Toxicity 0.000 abstract 1
- 230000002588 toxic effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- NCYLMOVCPMNHEP-UHFFFAOYSA-N 2,2-dimethylpropanediamide Chemical compound NC(=O)C(C)(C)C(N)=O NCYLMOVCPMNHEP-UHFFFAOYSA-N 0.000 description 20
- 238000012360 testing method Methods 0.000 description 12
- 238000012545 processing Methods 0.000 description 7
- 239000000047 product Substances 0.000 description 6
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 description 5
- 206010020772 Hypertension Diseases 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 229960004601 aliskiren Drugs 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229960004756 ethanol Drugs 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 102000008946 Fibrinogen Human genes 0.000 description 3
- 108010049003 Fibrinogen Proteins 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- -1 carbobenzoxy-(Cbz) Chemical class 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 229940012952 fibrinogen Drugs 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- 229910021529 ammonia Inorganic materials 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 101710129690 Angiotensin-converting enzyme inhibitor Proteins 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 101710086378 Bradykinin-potentiating and C-type natriuretic peptides Proteins 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- RBHJBMIOOPYDBQ-UHFFFAOYSA-N carbon dioxide;propan-2-one Chemical compound O=C=O.CC(C)=O RBHJBMIOOPYDBQ-UHFFFAOYSA-N 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000007096 poisonous effect Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an industrial method for preparing 3- amino- 2, 2- bimethyl propionamide, which is a segment in high pressure protein proenzyme inhibitor. The invention takes normal and cheapcyanoacetamide as raw material, alkalyating two nethyls, catalytic hydrogenating or adding reducant agent and getting 3- amnio- 2, 2- bimethyl propionamide. The chenmical reaction is shown in the graph. The invention solves problems of difficulty of getting raw material, low productivity and long process line, needs no column chromatography and purification, avoids toxic potassium cyanide and realizes large scale production.
Description
Technical field:
The present invention relates to the fragment 3-amino-2 of hypertension fibrinogen inhibitor Aliskiren, the synthetic industrialized process for preparing of the two methyl propanamides of 2-.
Background technology:
Depressor Aliskiren is a kind of hypertension fibrinogen inhibitor, and Switzerland Speedel company has finished the I phase and the II phase clinical study work of hypertension therapeutic at present.II phase clinical assessment has been finished in the research of this medicine in congestive heart failure and chronic kidney hypofunction treatment simultaneously.Speedel company point out Aliskiren be first will enter III phase clinical study can be oral hypertension fibrinogen inhibitor.Novartis company will subsidize its III phase clinical study and be responsible for the registration work from now on of this medicine.Aliskiren acts on beginning most of renin-angiotensin system, is different from existing drug effect in angiotensin converting enzyme inhibitor and angiotensin II receptor antagonist, and the brand-new approach of blocking-up feritin angiotensin system is provided.
Because Aliskiren has the effect of good clinical treatment hypertension and chronic nephropathy, enjoy each big drugmaker to attract attention at present.The latter end fragment that a key is arranged in its structure is by 3-amino-2, and the two methyl propanamides of 2-make up.
At present document does not have that suitable method is synthesized and this compounds of purifying.Document had once been reported two kinds of preparation methods, and a kind of method is at first to react with potassium cyanide with 1-nitro iso-butylene, gets 3-amino-2 with iron powder reducing then, and the two methyl propanamides of 2-(J.Chem.Soc.1947,1500-1503).Another kind method is from N-maloyl imines, behind the last carbobenzoxy-(Cbz) with 3-amino-2, the transesterify of 2-dimethyl propyl alcohol generation ammonia obtains N-carbobenzoxy-(Cbz)-3-amino-2,2-dimethyl propyl alcohol, it gets N-carbobenzoxy-(Cbz)-3-amino-2 by sodium periodate and ruthenium trichloride oxidation, the 2-neopentanoic acid, N-carbobenzoxy-(Cbz)-3-amino-2,2-neopentanoic acid and ammoniacal liquor condensation obtain N-carbobenzoxy-(Cbz)-3-amino-2, the two methyl propanamides of 2-, thereafter be that catalyst hydrogenation is taken off carbobenzoxy-(Cbz) and obtained 3-amino-2 with palladium carbon, the two methyl propanamides (EP1548024A1) of 2-.
Document synthetic route 1:
Said synthesis route 1 is not suitable for the technical scale batch reaction, this be because:
(a) raw material that uses is not easy to obtain, and market does not have and sells, and need obtain by synthetic, and the building-up reactions difficulty is big;
(b) can generate more by product after the reduction reaction, cause the aftertreatment technology complexity, need the last product of column chromatography purification, resulting product yield (having only about 5%) and product purity can not be satisfactory for plant-scale preparation method;
(c) hypertoxic reagent potassium cyanide has been used in reaction in addition, and is also totally unfavorable to labour protection, environment protection.
Document synthetic route 2:
Said synthesis route 2 is not suitable for the technical scale batch reaction, this be because:
(a) synthetic route is long;
(b) in the synthetic route, the ammonia transesterify needs column chromatography purification;
(c) in the synthetic route, oxidation time is long, needs 3 day time, is unfavorable for the industrial production of mass-producing.
Summary of the invention:
The technical issues that need to address of the present invention are: solved existing 3-amino-2, among the two methyl propanamide preparation technologies of 2-desired raw material rare, need column chromatography purification and use poisonous reagent potassium cyanide, problem that can't large-scale production; Provide a kind of 3-amino-2 brand-new, that easy, the whole yield of step is higher, preparation cost is lower, the large-scale industrial preparation method of the two methyl propanamides of 2-.
Technical scheme of the present invention:
The present invention is a raw material with malonamide nitrile conventional, that be easy to get, obtains 3-amino-2 by two methyl, shortenings in the alkylation or after adding the reductive agent reduction, the two methyl propanamides of 2-.
Concrete synthesis technique of the present invention is as follows:
In above-mentioned technological process, we adopt sodium ethylate to do alkali, capture the hydrogen on the other methylene radical of malonamide nitrile carbonyl, add a kind of in methylating reagent methyl iodide, the methyl-sulfate again, and solvent can be selected a kind of in ethanol, the methyl alcohol for use; Temperature of reaction is a normal temperature to 80 ℃.
In the shortening process, we adopt conventional hydrogenation catalyst, a kind of as in Raney's nickel, the palladium carbon, the reaction consumption is 5～20% (W/W) of reaction substrate, solvent is a kind of in ethanol, the methyl alcohol, or uses mixed solvent such as ethanol and ammoniacal liquor, a kind of in methyl alcohol and the ammoniacal liquor; Reaction pressure is 1～10 normal atmosphere, and optimal pressure range is between 2～5 normal atmosphere; Temperature of reaction is a normal temperature to 80 ℃, and optimum temps is 40～60 ℃.We also can adopt other reductive agent in this step, a kind of as in Lithium Aluminium Hydride, borine, the borine dimethyl sulphide, and solvent is a kind of in anhydrous tetrahydro furan, the anhydrous diethyl ether; Temperature of reaction be-78 ℃ to normal temperature.
Beneficial effect of the present invention:
Reaction process of the present invention is selected rationally, it has adopted the malonamide nitrile that economy on sale is easy to get on the Chemical market is raw material, obtain 3-amino-2 by two methyl, shortenings in the alkylation or after adding the reductive agent reduction reaction, the two methyl propanamides of 2-, its overall yield can reach 53～74%.The present invention has shortened in the document because the processing step that synthesis material causes, reaction is control easily, and preparation cost is lower, and intermediate can reach purification by solvent wash, therefore can carry out large-scale industrial production.
Embodiment:
The following example helps to understand the present invention, but is not limited to content of the present invention.
Embodiment 1
3-amino-2, the two methyl propanamides of 2-synthetic:
The first step: dimethyl malonamide nitrile synthetic
(204g 3mol) slowly joins in the 2000ml dehydrated alcohol sodium ethylate, adds the back and stirs half an hour, adds malonamide nitrile (84g then, 1mol), when 80 ℃ of interior temperature, refluxed 2 hours, be as cold as 30 ℃ then, the adding methyl iodide (426g, 3mol), enclosed system, room temperature reaction 12 hours.Solvent evaporated adds water 500ml, then with methylene dichloride 250ml extraction six times, combined dichloromethane layer, with saturated common salt washing, anhydrous sodium sulfate drying, be spin-dried for back 100ml washed with dichloromethane after-filtration, obtain filter cake and be the dimethyl malonamide nitrile (90g, 0.80mol), productive rate 80%.
1H?NMR(400MHz，DMSO-d
6)：δ7.63(brs，1H)，7.46(brs，1H)，1.58(s，6H)；MS(m/z)：113(M+H)
+。
Second step: 3-amino-2, the two methyl propanamides of 2-synthetic
(26.5g added ammoniacal liquor (40ml) and Raney Ni catalyzer (5.3g) in ethanol solution 0.237mol) (160ml), in 2 normal atmosphere, 60 ℃ of following hydrogenation 4 hours at the dimethyl malonamide nitrile.Remove by filter catalyzer, concentrate, get 3-amino-2, and the two methyl propanamides of 2-(25.3g, 0.218mol), productive rate 92%.
1H?NMR(400MHz，CDCl
3)：δ7.72(brs，1H)，5.58(brs，1H)，2.77(s，2H)，1.16(s，6H)；MS(m/z)：117(M+H)
+。
Embodiment 2
3-amino-2, the two methyl propanamides of 2-synthetic:
The first step: dimethyl malonamide nitrile synthetic
According to described processing condition of the first step and operation steps in the foregoing description 1, prepare the dimethyl malonamide nitrile, productive rate 80%, its test data is shown in above-mentioned embodiment 1 the first step.
Second step: 3-amino-2, the two methyl propanamides of 2-synthetic
(5.6g 0.05mol) in molten and the absolute methanol solution (40ml), added ammoniacal liquor (10ml) and Raney Ni catalyzer (1.1g), in 10 normal atmosphere, 40 ℃ of following hydrogenation 3 hours with the dimethyl malonamide nitrile.Remove by filter catalyzer, concentrate, get 3-amino-2, and the two methyl propanamides of 2-(5.2g, 0.045mol), productive rate 90%.Its test data is shown in above-mentioned 1 second step of embodiment.
Embodiment 3
3-amino-2, the two methyl propanamides of 2-synthetic:
The first step: dimethyl malonamide nitrile synthetic
According to described processing condition of the first step and operation steps in the foregoing description 1, prepare the dimethyl malonamide nitrile, productive rate 80%, its test data is shown in above-mentioned embodiment 1 the first step.
Second step: 3-amino-2, the two methyl propanamides of 2-synthetic
(5.6g 0.05mol) in molten and the absolute methanol solution (40ml), added 5% Pd/C catalyzer (0.28g), in 3 normal atmosphere, 60 ℃ of following hydrogenation 3 hours with the dimethyl malonamide nitrile.Remove by filter catalyzer, concentrate, get 3-amino-2, and the two methyl propanamides of 2-(5.0g, 0.043mol), productive rate 86%.Its test data is shown in above-mentioned 1 second step of embodiment.
Embodiment 4
3-amino-2, the two methyl propanamides of 2-synthetic:
The first step: dimethyl malonamide nitrile synthetic
Sodium ethylate (204g, 3mol) slowly join in the 2000ml anhydrous methanol, add the back and stir half an hour, add malonamide nitrile (84g then, 1mol), when 65 ℃ of interior temperature, refluxed 2 hours, be as cold as 30 ℃ then, add methyl-sulfate (378g, 3mol), enclosed system, room temperature reaction 12 hours.Solvent evaporated, add water 500ml, with methylene dichloride 250ml extraction six times, the combined dichloromethane layer is washed with saturated common salt then, anhydrous sodium sulfate drying, be spin-dried for the back with 100mL washed with dichloromethane after-filtration, obtain that (87g, filter cake 0.75mol) are the dimethyl malonamide nitrile, productive rate 75%, its test data is shown in above-mentioned embodiment 1 the first step.
Second step: 3-amino-2, the two methyl propanamides of 2-synthetic
According to described processing condition of second step and operation steps in the foregoing description 1, prepare 3-amino-2, the two methyl propanamides of 2-.Productive rate 92%, its test data is shown in above-mentioned 1 second step of embodiment.
Embodiment 5
3-amino-2, the two methyl propanamides of 2-synthetic:
The first step: dimethyl malonamide nitrile synthetic
According to described processing condition of the first step and operation steps in the foregoing description 1, prepare the dimethyl malonamide nitrile, productive rate 80%, its test data is shown in above-mentioned embodiment 1 the first step.
Second step: 3-amino-2, the two methyl propanamides of 2-synthetic
(5.6g 0.05mol) is dissolved in the anhydrous tetrahydro furan (150ml), and reactor is replaced as nitrogen atmosphere, and (10M/L, 15ml 0.15mol), dropwised stirring at room 12 hours in about 10 minutes to drip the borine dimethyl sulphide with the dimethyl malonamide nitrile.Adding methyl alcohol (100ml) refluxed 2 hours, the borine dimethyl sulphide that cancellation is excessive, solvent evaporated adds water 80ml, use the mixed extractant solvent five times of methylene dichloride and Virahol (45ml/15ml) then, merge organic phase, anhydrous sodium sulfate drying, the methylene dichloride (10ml) with 0 ℃ after being spin-dried for washs after-filtration, get product (4.3g, 0.037mol), productive rate 74%, its test data is shown in above-mentioned 1 second step of embodiment.
Embodiment 6
3-amino-2, the two methyl propanamides of 2-synthetic:
The first step: dimethyl malonamide nitrile synthetic
According to described processing condition of the first step and operation steps in the foregoing description 1, prepare the dimethyl malonamide nitrile, productive rate 80%, its test data is shown in above-mentioned embodiment 1 the first step.
Second step: 3-amino-2, the two methyl propanamides of 2-synthetic
(5.6g 0.05mol) is dissolved in the anhydrous diethyl ether (150ml), and reactor is replaced as nitrogen atmosphere, and (1M/L, 150ml 0.15mol), dropwised stirring at room 12 hours in about 10 minutes to the tetrahydrofuran solution of dropping borine with the dimethyl malonamide nitrile.Adding methyl alcohol (100ml) refluxed 2 hours, the borine that cancellation is excessive, solvent evaporated adds water 100ml, use the mixed extractant solvent five times of methylene dichloride and Virahol (120ml/40ml) then, merge organic phase, anhydrous sodium sulfate drying, the methylene dichloride (10ml) with 0 ℃ after being spin-dried for washs after-filtration, get product (4.4g, 0.038mol), productive rate 76%, its test data is shown in above-mentioned 1 second step of embodiment.
Embodiment 7
3-amino-2, the two methyl propanamides of 2-synthetic:
The first step: dimethyl malonamide nitrile synthetic
According to described processing condition of the first step and operation steps in the foregoing description 1, prepare the dimethyl malonamide nitrile, productive rate 80%, its test data is shown in above-mentioned embodiment 1 the first step.
Second step: 3-amino-2, the two methyl propanamides of 2-synthetic
With Lithium Aluminium Hydride (7.6g, 0.2mol) be dissolved in the anhydrous tetrahydro furan (500ml), reactor is replaced as nitrogen atmosphere, when dry ice acetone bath is cooled to-78 ℃, (22.4g, anhydrous tetrahydro furan 0.2mol) (100ml) solution dropwised in about 10 minutes to drip the dimethyl malonamide nitrile, keep reacting liquid temperature in-78 ℃ of reactions 5 hours, slowly be warmed up to-78 ℃ of reactions 12 hours, after the TLC monitoring reaction finishes, keep reacting liquid temperature in-5 ℃, drip water and each 8ml of 10% sodium hydroxide solution, stir half an hour, suction filtration is dissolved in anhydrous methylene chloride after filtrate is spin-dried for, wash with saturated common salt, anhydrous sodium sulfate drying then, be spin-dried for the back with 0 ℃ methylene dichloride (50ml) wash the after-filtration product (15.3g, 0.132mol), productive rate 53%, its test data is shown in above-mentioned 1 second step of embodiment.
Claims (4)
1,3-amino-2, the two methyl propanamide synthetic industrialized process for preparing of 2-are raw material with malonamide nitrile conventional, that be easy to get, it is characterized in that, malonamide nitrile obtains 3-amino-2 by two methyl, shortenings in the alkylation or after adding the reductive agent reduction reaction, the two methyl propanamides of 2-; During two methyl react in described alkylation, adopt sodium ethylate to do alkali, capture the hydrogen on the other methylene radical of malonamide nitrile carbonyl, add a kind of in methylating reagent methyl iodide, the methyl-sulfate again, it is normal temperature to 80 ℃ that solvent is selected a kind of in ethanol, the methyl alcohol, temperature of reaction for use; In described shortening process, hydrogenation catalyst adopts a kind of in Raney's nickel, the palladium carbon, the reaction consumption is 5～20% of a reaction substrate weight, solvent is a kind of in ethanol, methyl alcohol, ethanol and ammoniacal liquor, methyl alcohol and the ammoniacal liquor, reaction pressure is 1～10 normal atmosphere, and temperature of reaction is a normal temperature to 80 ℃; Add in the reductive agent reduction reaction process described, it is a kind of in anhydrous tetrahydro furan, the anhydrous diethyl ether that reductive agent is selected a kind of in Lithium Aluminium Hydride, borine, the borine dimethyl sulphide, solvent for use, temperature of reaction be-78 ℃ to normal temperature.
2,3-amino-2 according to claim 1, the two methyl propanamide synthetic industrialized process for preparing of 2-is characterized in that the reaction formula of above-mentioned reaction is:
3,3-amino-2 according to claim 1, the two methyl propanamide synthetic industrialized process for preparing of 2-is characterized in that catalytic hydrogenation reaction pressure is 2～5 normal atmosphere.
4,3-amino-2 according to claim 1, the two methyl propanamide synthetic industrialized process for preparing of 2-is characterized in that the catalytic hydrogenation reaction temperature is 40～60 ℃.
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| JP2012522746A (en) | 2009-04-01 | 2012-09-27 | レツク・フアーマシユーテイカルズ・デー・デー | Method for dimethylation of active methylene groups |
| EP2459521A1 (en) | 2009-07-31 | 2012-06-06 | Sandoz AG | Method for the preparation of w-amino-alkaneamides and w-amino-alkanethioamides as well as intermediates of this method |
| CN102140068B (en) * | 2010-01-30 | 2015-03-11 | 浙江华海药业股份有限公司 | Preparation method of Aliskiren intermediate 3-amino-2,2-dimethylpropionamide |
| CN101863796B (en) * | 2010-05-12 | 2011-08-24 | 海南美兰史克制药有限公司 | Aliskiren compound and novel preparation method thereof |
| WO2012010651A2 (en) | 2010-07-23 | 2012-01-26 | Sandoz Ag | Method for the preparation of omega-amino-alkaneamides and omega-amino-alkanethioamides as well as intermediates of this method |
| CN102477002B (en) * | 2010-11-26 | 2015-04-15 | 苏州凯达生物医药技术有限公司 | Preparation method of 3-amino-2, 2-dimethylpropionamide |
| CN103145585B (en) * | 2011-12-07 | 2015-08-19 | 上海医药工业研究院 | A kind of preparation method of 2,2-dimethyl malonamide nitrile |
| CN103333082A (en) * | 2013-07-24 | 2013-10-02 | 常熟富士莱医药化工有限公司 | Preparation method for 3-amino-2, 2-dimethylpropionamide |
| CN104003900A (en) * | 2014-04-29 | 2014-08-27 | 南通常佑药业科技有限公司 | Synthesis method of hypertension protease inhibitor aliskiren intermediate 3-amino-2,2-dimethylpropionamide |
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