CN102477002B - Preparation method of 3-amino-2, 2-dimethylpropionamide - Google Patents
Preparation method of 3-amino-2, 2-dimethylpropionamide Download PDFInfo
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- CN102477002B CN102477002B CN201010561942.9A CN201010561942A CN102477002B CN 102477002 B CN102477002 B CN 102477002B CN 201010561942 A CN201010561942 A CN 201010561942A CN 102477002 B CN102477002 B CN 102477002B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- HKQZJXVIXAPOPZ-UHFFFAOYSA-N 3-amino-2,2-dimethylpropanamide Chemical compound NCC(C)(C)C(N)=O HKQZJXVIXAPOPZ-UHFFFAOYSA-N 0.000 title abstract description 5
- NGRPJOQCQYDOJX-UHFFFAOYSA-N 4-hydroxy-2,2-dimethylbutanoic acid Chemical compound OC(=O)C(C)(C)CCO NGRPJOQCQYDOJX-UHFFFAOYSA-N 0.000 claims abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 59
- QJQAMHYHNCADNR-UHFFFAOYSA-N n-methylpropanamide Chemical compound CCC(=O)NC QJQAMHYHNCADNR-UHFFFAOYSA-N 0.000 claims description 44
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 24
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 24
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 22
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 21
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 21
- 230000032050 esterification Effects 0.000 claims description 19
- 238000005886 esterification reaction Methods 0.000 claims description 19
- -1 pentyl ester Chemical class 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- RDFQSFOGKVZWKF-UHFFFAOYSA-N 3-hydroxy-2,2-dimethylpropanoic acid Chemical compound OCC(C)(C)C(O)=O RDFQSFOGKVZWKF-UHFFFAOYSA-N 0.000 claims description 12
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 12
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012346 acetyl chloride Substances 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000003513 alkali Substances 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 3
- 239000002075 main ingredient Substances 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 22
- 238000009776 industrial production Methods 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 description 45
- 238000003786 synthesis reaction Methods 0.000 description 45
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
- 238000001035 drying Methods 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 238000010992 reflux Methods 0.000 description 18
- UNOIUIVUMLPSGG-UHFFFAOYSA-N methyl 4-hydroxy-2,2-dimethylbutanoate Chemical class COC(=O)C(C)(C)CCO UNOIUIVUMLPSGG-UHFFFAOYSA-N 0.000 description 16
- 239000001301 oxygen Substances 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 10
- 229960003328 benzoyl peroxide Drugs 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 9
- 238000004821 distillation Methods 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 150000004702 methyl esters Chemical class 0.000 description 9
- 238000012544 monitoring process Methods 0.000 description 9
- 230000007935 neutral effect Effects 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 8
- 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
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical class CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 5
- 229960004601 aliskiren Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- JBDMHPJPFPMZLI-UHFFFAOYSA-N ethyl 3-hydroxy-2,2-dimethylpropanoate Chemical compound CCOC(=O)C(C)(C)CO JBDMHPJPFPMZLI-UHFFFAOYSA-N 0.000 description 4
- WJOKYRVCHGXWDJ-UHFFFAOYSA-N ethyl 4-hydroxy-2,2-dimethylbutanoate Chemical compound CCOC(=O)C(C)(C)CCO WJOKYRVCHGXWDJ-UHFFFAOYSA-N 0.000 description 4
- 125000004494 ethyl ester group Chemical group 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- JQWHASGSAFIOCM-UHFFFAOYSA-M sodium periodate Chemical compound [Na+].[O-]I(=O)(=O)=O JQWHASGSAFIOCM-UHFFFAOYSA-M 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 description 3
- 239000002532 enzyme inhibitor Substances 0.000 description 3
- 0 CC(C)(C*(*)=C)C(*N)=O Chemical compound CC(C)(C*(*)=C)C(*N)=O 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000001035 methylating effect Effects 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N n-propyl alcohol Natural products CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 2
- UNEVQPDIKBMDRY-UHFFFAOYSA-N propan-2-yl 4-hydroxy-2,2-dimethylbutanoate Chemical compound CC(C)OC(=O)C(C)(C)CCO UNEVQPDIKBMDRY-UHFFFAOYSA-N 0.000 description 2
- YBCAZPLXEGKKFM-UHFFFAOYSA-K ruthenium(iii) chloride Chemical compound [Cl-].[Cl-].[Cl-].[Ru+3] YBCAZPLXEGKKFM-UHFFFAOYSA-K 0.000 description 2
- 238000004904 shortening Methods 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
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 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
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000020832 chronic kidney disease Diseases 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000010970 precious metal Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- QWYHNBGEJNPGDW-UHFFFAOYSA-N propan-2-yl 3-hydroxy-2,2-dimethylpropanoate Chemical compound CC(C)OC(=O)C(C)(C)CO QWYHNBGEJNPGDW-UHFFFAOYSA-N 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 230000036454 renin-angiotensin system Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 231100000004 severe toxicity Toxicity 0.000 description 1
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical compound [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
Abstract
The invention discloses a preparation method of 3-amino-2, 2-dimethylpropionamide. Hydroxymethyl trimethylacetic acid which can be easily obtained in market supply is used as a raw material which is esterified, protected, and ammonolyzed to obtain the 3-amino-2, 2-dimethylpropionamide. The preparation method has the advantages that the route is reasonable, raw materials are obtained easily, cost is low, yield is high, operation is simple and the like. In addition, the preparation method effectively meets requirements of industrial production.
Description
Technical field
The present invention relates to medicine preparation, particularly the preparation method of the two methyl propanamide of a fragment 3-amino-2,2-of a kind of angiotonin enzyme inhibitors Aliskiren.
Background technology
Depressor Aliskiren is a kind of angiotonin enzyme inhibitors, and Speedel company of current Switzerland has completed I phase and the II phase clinical work of hypertension therapeutic.The research of this medicine in congestive heart failure and chronic kidney hypofunction treatment simultaneously has completed II phase clinical assessment.Speedel company point out Aliskiren be first by enter III phase clinical study can be oral angiotonin enzyme inhibitors.Its III phase clinical study of subsidy is also responsible for the registration work from now on of this medicine by Novartis company.Aliskiren acts on starting most of renin angiotensin system, is different from existing drug effect in angiotensin converting enzyme inhibitor and angiotensin II receptor antagonist, provides the brand-new approach blocking feritin angiotensin system.
Because Aliskiren has good clinical treatment hypertension and the effect of chronic renal failure, enjoy the concern of Ge great drugmaker at present.The two such critical segment of methyl propanamide of 3-amino-2,2-is contained in this medicines structure.As shown below:
Current document has 3 kinds of methods to prepare the two methyl propanamide of 3-amino-2,2-.
Method one: 1-nitro iso-butylene and potassium cyanide react, and then reduce in acid condition with iron powder and obtain the two methyl propanamide (J.Chem.Soc.1947,1500-1503) of 3-amino-2,2-, reaction formula is as follows:
There is following shortcoming in this reaction, restricts its suitability for industrialized production:
(1) reaction employs the potassium cyanide of severe toxicity, and the requirement for operation and environment is very high, needs certain qualification;
(2) react starting raw material to be not easy to obtain, need oneself to synthesize;
(3) by product reacted is more, needs column chromatography to purify, and products therefrom yield 5% is not suitable for large production.
Method two: with N-hydroxysuccinimide for raw material; N-protects with carbobenzoxy-(Cbz); then with 3-amino-2; 2-dimethyl propyl alcohol is obtained by reacting N-carbobenzoxy-(Cbz)-3-amino-2; 2-dimethyl propyl alcohol; N-carbobenzoxy-(Cbz)-3-amino-2 is obtained again with sodium periodate and ruthenium trichloride oxidation; 2-neopentanoic acid; N-carbobenzoxy-(Cbz)-3-amino-2 is obtained again with ammoniacal liquor condensation; 2-dimethylpropionamide; last shortening obtains 3-amino-2,2-dimethylpropionamide (EP:1548024A1), and reaction formula is as follows:
There is following shortcoming in this reaction, restricts its suitability for industrialized production:
(1) use sodium periodate, ruthenium trichloride oxidation alcohol, cost is very high, and long reaction time, needs 3 days;
(2) taking off carbobenzoxy-(Cbz) protection needs precious metals pd/C to make catalyzer, and cost is high;
(3) ammonia transesterification reaction needs column chromatography to purify, and is not suitable for large production.
Method three: take malonamide nitrile as raw material, two methyl are gone up in the basic conditions with methylating reagent, then reduce under shortening eats pressure condition with Raney Ni and obtain the two methyl propanamide (CN1990461A) of 3-amino-2,2-, reaction formula is as follows:
There is following shortcoming in this reaction, restricts its suitability for industrialized production:
(1) use methylating reagent methyl iodide for easy drugs processed, raw material is difficult to buying;
(2) cyano group that reduces needs pressure reaction still, and cost is large, is not suitable for large production.
Summary of the invention
For solving the problem, the object of the invention is to overcome above-mentioned deficiency, there is provided and the object of this invention is to provide a kind of 3-amino-2, the preparation method of the two methyl propanamide of 2-, it has, and route is reasonable, raw material is easy to get, cost is lower, yield is higher, simple operation and other advantages, is more suitable for the needs of suitability for industrialized production.
For achieving the above object, technical scheme of the present invention is: the preparation method of the two methyl propanamide of a kind of 3-amino-2,2-, and the two methyl propanamide of described 3-amino-2,2-has structure shown in formula one, and formula one is as follows:
its preparation order is as follows:
Preferably, comprise the following steps:
Step one, esterification, by methylol trimethylacetic acid esterification in the solvent be applicable to and under acid catalysed conditions, obtain the special pentyl ester of methylol of structure shown in formula two, formula two is as follows:
Step 2, protection, special for the methylol obtained in step 2 pentyl ester and acyl chlorides and alkali are reacted in a suitable solvent, obtain the compound of structure shown in formula three, formula three is as follows:
Step 3, ammonia solution, carries out the operation of ammonia solution by the compound obtained in step 2, obtains the formula one i.e. two methyl propanamide of described 3-amino-2,2-.
Preferably, described in step one, described suitable solvent can be alcohols, as methyl alcohol, ethanol or Virahol; Described acid is hydrochloric acid, sulfuric acid, tosic acid or sodium pyrosulfate.
Preferably, the described SULPHURYL CHLORIDE described in step 2 can be Acetyl Chloride 98Min., Benzoyl chloride, methylsulfonyl chloride, to the yellow acyl chlorides of toluene or trifluoromethanesulfchloride chloride; Suitable solvent is for being methylene dichloride, 1,2-ethylene dichloride, pyridine or Isosorbide-5-Nitrae-dioxane; Described alkali is sodium carbonate, salt of wormwood, pyridine, sodium hydroxide or potassium hydroxide.
Preferably, the ammonia solution described in step 3 is operating as and ammoniacal liquor or ammonia gas react.
Preferably, in each step 3, each main ingredient mol ratio is:
Step one, esterification: hydroxypivalic acid: solvent=1: 2-1: 10; Step 2, protection: hydroxypivalic acid ester: acyl chlorides=1: 1.1-1: 2; Step 3, ammonia solution: protection ester: strong aqua=1: 30-1: 60.
The beneficial effect of employing the technical program is: the preparation method of the two methyl propanamides of a kind of 3-of the present invention amino-2,2-, and the methylol trimethylacetic acid be easy to get with market supply is raw material, and through esterification, protection, ammonia solution 3 step is obtained by reacting 3-amino-2,2-pairs of methyl propanamides.Have route rationally, raw material is easy to get, cost is lower, yield is higher, simple operation and other advantages, is more suitable for the needs of suitability for industrialized production.
Embodiment
Below in conjunction with the drawings and specific embodiments, the present invention is further detailed explanation.
Embodiment 1,
The preparation method of the two methyl propanamide of a kind of 3-amino-2,2-, the methylol trimethylacetic acid be easy to get with market supply is raw material, and through esterification, protection, ammonia solution 3 step is obtained by reacting the two methyl propanamide of 3-amino-2,2-.
The concrete reaction equation of the present invention is as follows:
The preparation method of the two methyl propanamide of a kind of 3-amino-2,2-, the methylol trimethylacetic acid be easy to get with market supply is raw material, and through esterification, protection, ammonia solution 3 step is obtained by reacting the two methyl propanamide of 3-amino-2,2-.
The concrete reaction equation of the present invention is as follows:
Concrete steps are as follows:
Step one, esterification, the i.e. synthesis of methylol trimethylacetic acid methyl esters:
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, methyl alcohol 800mL and the 5mL vitriol oil, reflux 6h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid methyl esters 372 grams, productive rate: 74%, GC:99.8%.
Step 2, protection, i.e. the synthesis of 3-mesyloxy-PA methyl esters:
Methylol trimethylacetic acid methyl esters (13.2g, 0.1mol) of above-mentioned synthesis is dissolved in pyridine 100ml, adds DMAP1.0g, hierarchy of control temperature less than 0 DEG C drips methylsulfonyl chloride (13.7g, 0.12mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 8h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filters, and concentrates and obtains 3-mesyloxy-2,2-dimethylated methyl propionate 19.3g, yield 92%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
The 3-of above-mentioned synthesis mesyloxy-PA methyl esters (21.0g, 0.1mol) is joined in the strong aqua 250ml of 28%, reflux 5h, cool to room temperature, adds that 100ml toluene band water is concentrated obtains 3-amino-2, the two methyl propanamide 9.86g of 2-, yield 85%.
Embodiment 2,
Step one, esterification, the i.e. synthesis of methylol trimethylacetic acid methyl esters:
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, methyl alcohol 800mL and the 5mL vitriol oil, reflux 6h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid methyl esters 372 grams, productive rate: 74%, GC:99.8%.
Step 2, protection, i.e. the synthesis of 3-tolysulfonyl oxygen base-PA methyl esters:
Methylol trimethylacetic acid methyl esters (13.2g, 0.1mol) of above-mentioned synthesis is dissolved in pyridine 100ml, adds DMAP2.0g, hierarchy of control temperature less than 0 DEG C adds Tosyl chloride (22.9g in batches, 0.12mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 16h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filters, and concentrates and obtains 3-tolysulfonyl oxygen base-2,2-dimethylated methyl propionate 26.3g, yield 92%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
By the 3-tolysulfonyl oxygen base-2 of above-mentioned synthesis, 2-dimethylated methyl propionate (28.6g, 0.1mol) join in the strong aqua 250ml of 28%, reflux 6h, cool to room temperature, add that 100ml toluene band water is concentrated obtains the two methyl propanamide 9.28g of 3-amino-2,2-, yield 80%.
Embodiment 3,
Step one, esterification, the i.e. synthesis of methylol trimethylacetic acid methyl esters:
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, methyl alcohol 800mL and the 5mL vitriol oil, reflux 6h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid methyl esters 372 grams, productive rate: 74%, GC:99.8%.
Step 2, protection, i.e. the synthesis of 3-tolysulfonyl oxygen base-PA methyl esters:
By the methylol trimethylacetic acid methyl esters (13.2g of above-mentioned synthesis, 0.1mol) be dissolved in 1, in 2-ethylene dichloride 80ml, add DMAP5.0g and salt of wormwood (27.6g, 0.2mol), hierarchy of control temperature less than 0 DEG C adds Tosyl chloride (22.9g in batches, 0.12mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 18h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filters, and concentrates and obtains 3-tolysulfonyl oxygen base-2,2-dimethylated methyl propionate 22.3g, yield 78%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
By the 3-tolysulfonyl oxygen base-2 of above-mentioned synthesis, 2-dimethylated methyl propionate (28.6g, 0.1mol) join in the strong aqua 250ml of 28%, reflux 6h, cool to room temperature, add that 100ml toluene band water is concentrated obtains the two methyl propanamide 9.28g of 3-amino-2,2-, yield 80%.
Embodiment 4,
Step one, esterification, the i.e. synthesis of methylol trimethylacetic acid ethyl ester:
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, ethanol 900mL and the 5mL vitriol oil, reflux 8h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid ethyl ester 416.6 grams, productive rate: 75%, GC:99.6%.
Step 2, protection, i.e. the synthesis of 3-acetoxyl group-PA methyl esters:
By the methylol trimethylacetic acid methyl esters (13.2g of above-mentioned synthesis, 0.1mol) be dissolved in pyridine 100ml, hierarchy of control temperature less than 0 DEG C drips Acetyl Chloride 98Min. (9.4g, 0.12mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 0.5-2h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrate and obtain 3-acetoxyl group-PA methyl esters 15.6g, yield 90%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
The 3-of above-mentioned synthesis acetoxyl group-PA methyl esters (17.4g, 0.1mol) is joined in the strong aqua 250ml of 28%, reflux 8h, cool to room temperature, adds that 100ml toluene band water is concentrated obtains 3-amino-2, the two methyl propanamide 6.96g of 2-, yield 60%.
Embodiment 5,
Step one, esterification, the i.e. synthesis of hydroxypivalic acid isopropyl ester
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, Virahol 1000mL and the 5mL vitriol oil, reflux 18h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid isopropyl ester 425.6 grams, productive rate: 70%, GC:99.1%.
Step 2, protection, i.e. the synthesis of 3-acetoxyl group-PA isopropyl ester:
By the methylol trimethylacetic acid isopropyl ester (16.0g of above-mentioned synthesis, 0.1mol) be dissolved in pyridine 100ml, hierarchy of control temperature less than 0 DEG C drips Acetyl Chloride 98Min. (9.4g, 0.12mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 0.5-2h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrate and obtain 3-acetoxyl group-PA isopropyl ester 17.2g, yield 85%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
The 3-of above-mentioned synthesis acetoxyl group-PA isopropyl ester (20.2g, 0.1mol) is joined in the strong aqua 250ml of 28%, reflux 8h, cool to room temperature, adds that 100ml toluene band water is concentrated obtains 3-amino-2, the two methyl propanamide 6.8g of 2-, yield 58.6%.
Embodiment 6,
Step one, esterification, the i.e. synthesis of hydroxypivalic acid ethyl ester
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, ethanol 900mL and the 5mL vitriol oil, reflux 8h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid ethyl ester 416.6 grams, productive rate: 75%, GC:99.6%.
Step 2, protection, i.e. the synthesis of 3-acetoxyl group-PA ethyl ester:
By the hydroxypivalic acid ethyl ester (14.6g of above-mentioned synthesis, 0.1mol) be dissolved in pyridine 100ml, hierarchy of control temperature less than 0 DEG C drips Acetyl Chloride 98Min. (9.4g, 0.12mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 0.5-2h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrate and obtain 3-acetoxyl group-PA ethyl ester 16.9g, yield 89%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
The 3-of above-mentioned synthesis acetoxyl group-PA ethyl ester (18.8g, 0.1mol) is joined in the strong aqua 250ml of 28%, reflux 8h, cool to room temperature, adds that 100ml toluene band water is concentrated obtains 3-amino-2, the two methyl propanamide 6.35g of 2-, yield 54.7%.
Embodiment 7,
Step one, esterification, the i.e. synthesis of hydroxypivalic acid ethyl ester
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, ethanol 900mL and the 5mL vitriol oil, reflux 8h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid ethyl ester 416.6 grams, productive rate: 75%, GC:99.6%.
Step 2, protection, i.e. the synthesis of 3-mesyloxy-PA ethyl ester:
The hydroxypivalic acid ethyl ester (14.6g, 0.1mol) of above-mentioned synthesis is dissolved in pyridine 100ml, adds DMAP1.0g, hierarchy of control temperature less than 0 DEG C drips methylsulfonyl chloride (13.7g, 0.12mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 10h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filters, and concentrates and obtains 3-mesyloxy-2,2-ethyl dimethyl 28.0g, yield 82%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
By the 3-mesyloxy-2 of above-mentioned synthesis, 2-ethyl dimethyl (22.4g, 0.1mol) join in the strong aqua 250ml of 28%, reflux 5h, cool to room temperature, add that 100ml toluene band water is concentrated obtains the two methyl propanamide 9.82g of 3-amino-2,2-, yield 84.6%.
Embodiment 8,
Step one, esterification, the i.e. synthesis of methylol trimethylacetic acid methyl esters:
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, methyl alcohol 330mL and the 5mL vitriol oil, reflux 6h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid methyl esters 281 grams, productive rate: 56%, GC:98.3%.
Step 2, protection, i.e. the synthesis of 3-tolysulfonyl oxygen base-PA methyl esters:
Methylol trimethylacetic acid methyl esters (13.2g, 0.1mol) of above-mentioned synthesis is dissolved in pyridine 100ml, adds DMAP2.0g, hierarchy of control temperature less than 0 DEG C adds Tosyl chloride (21g in batches, 0.11mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 16h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filters, and concentrates and obtains 3-tolysulfonyl oxygen base-2,2-dimethylated methyl propionate 25.0g, yield 90%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
By the 3-tolysulfonyl oxygen base-2 of above-mentioned synthesis, 2-dimethylated methyl propionate (28.6g, 0.1mol) join in the strong aqua 182ml of 28%, reflux 6h, cool to room temperature, add that 100ml toluene band water is concentrated obtains the two methyl propanamide 8.2g of 3-amino-2,2-, yield 70.6%.
Embodiment 9,
Step one, esterification, the i.e. synthesis of methylol trimethylacetic acid methyl esters
In the three-necked flask of a 2L, add (450g, 3.8mol) hydroxypivalic acid, methyl alcohol 1650mL and the 5mL vitriol oil, reflux 6h, GC monitoring reacts completely, without raw material.Cool to room temperature, transfers in single port flask and steams except methyl alcohol, and reclaim.Add sodium carbonate solution and regulate pH=8, extract with ethyl acetate 500mL × 4, merge organic phase, anhydrous sodium sulfate drying, filter, concentrated.Underpressure distillation obtains methylol trimethylacetic acid methyl esters 366.3 grams, productive rate: 73%, GC:99.2%.
Step 2, protection, i.e. the synthesis of 3-tolysulfonyl oxygen base-PA methyl esters:
Methylol trimethylacetic acid methyl esters (13.2g, 0.1mol) of above-mentioned synthesis is dissolved in pyridine 100ml, adds DMAP2.0g, hierarchy of control temperature less than 0 DEG C adds Tosyl chloride (38.2g in batches, 0.2mol), neutral with 10% dilute hydrochloric acid furnishing after stirred at ambient temperature 16h, extract with ethyl acetate 100mL × 4, merge organic phase, anhydrous sodium sulfate drying, filters, and concentrates and obtains 3-tolysulfonyl oxygen base-2,2-dimethylated methyl propionate 26.0g, yield 91%.
Step 3, ammonia solution, the i.e. synthesis of the two methyl propanamide of 3-amino-2,2-:
By the 3-tolysulfonyl oxygen base-2 of above-mentioned synthesis, 2-dimethylated methyl propionate (28.6g, 0.1mol) join in the strong aqua 364ml of 28%, reflux 6h, cool to room temperature, add that 100ml toluene band water is concentrated obtains the two methyl propanamide 9.2g of 3-amino-2,2-, yield 79%.
In above-described embodiment, in each step 3, each main ingredient mol ratio is: step one, esterification: hydroxypivalic acid: solvent=1: 2-1: 10; Step 2, protection: hydroxypivalic acid ester: acyl chlorides=1: 1.1-1: 2; Step 3, ammonia solution: protection ester: strong aqua=1: 30-1: 60.
The beneficial effect of employing the technical program is: the preparation method of the two methyl propanamides of a kind of 3-of the present invention amino-2,2-, and the methylol trimethylacetic acid be easy to get with market supply is raw material, and through esterification, protection, ammonia solution 3 step is obtained by reacting 3-amino-2,2-pairs of methyl propanamides.Have route rationally, raw material is easy to get, cost is lower, yield is higher, simple operation and other advantages, is more suitable for the needs of suitability for industrialized production.
Above-described is only the preferred embodiment of the present invention, it should be pointed out that for the person of ordinary skill of the art, and without departing from the concept of the premise of the invention, can also make some distortion and improvement, these all belong to protection scope of the present invention.
Claims (6)
1. the preparation method of the two methyl propanamide of 3-amino-2,2-, the two methyl propanamide of described 3-amino-2,2-has structure shown in formula one, and formula one is as follows:
it is characterized in that, its preparation order is as follows:
Wherein, R-OH is methyl alcohol, ethanol, Virahol, and R '-C1 is methylsulfonyl chloride, Tosyl chloride, Acetyl Chloride 98Min..
2. the preparation method of the two methyl propanamide of 3-amino-2,2-as claimed in claim 1, is characterized in that, comprise the following steps:
Step one, esterification, by methylol trimethylacetic acid esterification in the solvent be applicable to and under acid catalysed conditions, obtain the special pentyl ester of methylol of structure shown in formula two, formula two is as follows:
Step 2, protection, special for the methylol obtained in step one pentyl ester and acyl chlorides and alkali are reacted in a suitable solvent, namely the compound obtaining structure shown in formula three protects fat, and formula three is as follows:
Step 3, ammonia solution, carries out the operation of ammonia solution by the compound obtained in step 2, obtains the formula one i.e. two methyl propanamide of described 3-amino-2,2-.
3. the preparation method of the two methyl propanamide of 3-according to claim 2 amino-2,2-, it is characterized in that, solvent suitable described in step one is methyl alcohol, ethanol or Virahol; Described acid is hydrochloric acid, sulfuric acid or tosic acid.
4. the preparation method of the two methyl propanamide of 3-according to claim 2 amino-2,2-, it is characterized in that, the SULPHURYL CHLORIDE described in step 2 is methylsulfonyl chloride, Tosyl chloride or Acetyl Chloride 98Min.; Suitable solvent is methylene dichloride, 1,2-ethylene dichloride, pyridine or Isosorbide-5-Nitrae-dioxane; Described alkali is sodium carbonate, salt of wormwood, pyridine, sodium hydroxide or potassium hydroxide.
5. the preparation method of the two methyl propanamide of 3-according to claim 2 amino-2,2-, it is characterized in that, the ammonia solution described in step 3 is operating as reacts with ammoniacal liquor.
6., according to the preparation method of the two methyl propanamide of the arbitrary described 3-of claim 2 to 5 amino-2,2-, it is characterized in that, in each step, main ingredient mol ratio is:
Step one, hydroxypivalic acid: solvent=1: 2-1: 10;
Step 2, hydroxypivalic acid ester: acyl chlorides=1: 1.1-1: 2;
Step 3, protection ester: strong aqua=1: 30-1: 60.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1054598A (en) * | 1990-03-06 | 1991-09-18 | 詹森药业有限公司 | The preparation method of carboxamides derivatives |
| CN1990461A (en) * | 2005-12-27 | 2007-07-04 | 上海药明康德新药开发有限公司 | Industrial preparation method for 3-amino-2, 2-dimethyl propionamide |
| CN101575300A (en) * | 2009-06-11 | 2009-11-11 | 绍兴文理学院 | Production method of S-2-aminobutanamide |
-
2010
- 2010-11-26 CN CN201010561942.9A patent/CN102477002B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1054598A (en) * | 1990-03-06 | 1991-09-18 | 詹森药业有限公司 | The preparation method of carboxamides derivatives |
| CN1990461A (en) * | 2005-12-27 | 2007-07-04 | 上海药明康德新药开发有限公司 | Industrial preparation method for 3-amino-2, 2-dimethyl propionamide |
| CN101575300A (en) * | 2009-06-11 | 2009-11-11 | 绍兴文理学院 | Production method of S-2-aminobutanamide |
Non-Patent Citations (4)
| Title |
|---|
| Kinetic and equilibrium studies of the σ-adduct forming reactions of 1,3,5-trinitrobenzene and picryl chloride with some carbon bases;MICHAEL R,et al;《canadian journal of chemistry》;19861231;第64卷(第9期);1714-20 * |
| 王彦广.羧酸衍生物的水解,氨解和醇解.《有机化学》.2004,234-235. * |
| 蒋登高.氨解反应.《精细有机合成反应及工艺》.2001,214-216. * |
| 黄仲九.羟基化合物的氨解.《化学工艺学》.2001,608-612. * |
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