CN114805177B - Preparation method of saxagliptin intermediate - Google Patents
Preparation method of saxagliptin intermediate Download PDFInfo
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- CN114805177B CN114805177B CN202210459826.9A CN202210459826A CN114805177B CN 114805177 B CN114805177 B CN 114805177B CN 202210459826 A CN202210459826 A CN 202210459826A CN 114805177 B CN114805177 B CN 114805177B
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- 229960004937 saxagliptin Drugs 0.000 title claims abstract description 51
- 108010033693 saxagliptin Proteins 0.000 title claims abstract description 51
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 title claims abstract description 50
- 238000002360 preparation method Methods 0.000 title claims abstract description 31
- 238000006243 chemical reaction Methods 0.000 claims abstract description 21
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 14
- 230000004913 activation Effects 0.000 claims abstract description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims abstract description 7
- 239000000126 substance Substances 0.000 claims abstract description 7
- ZQSMZFIOPBRRKZ-SRQIZXRXSA-N (1s,3s,5s)-2-azabicyclo[3.1.0]hexane-3-carbonitrile Chemical compound N1[C@H](C#N)C[C@@H]2C[C@@H]21 ZQSMZFIOPBRRKZ-SRQIZXRXSA-N 0.000 claims abstract description 4
- 239000004471 Glycine Substances 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000000203 mixture Substances 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 12
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- -1 amino-protected (1S, 3S, 5S) -2- [ (2S) -2-amino-2- (3-hydroxyadamantan-1-yl) acetyl ] -2-azabicyclo [3.1.0] hexane-3-carbonitrile Chemical group 0.000 claims description 9
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 239000003513 alkali Substances 0.000 claims description 6
- 238000010976 amide bond formation reaction Methods 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 239000002274 desiccant Substances 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- 150000002576 ketones Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 3
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 2
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 239000004215 Carbon black (E152) Substances 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 2
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 238000002425 crystallisation Methods 0.000 claims description 2
- 230000008025 crystallization Effects 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 claims description 2
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 2
- FVSKHRXBFJPNKK-UHFFFAOYSA-N propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims description 2
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 abstract description 12
- 239000002994 raw material Substances 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 6
- 238000003912 environmental pollution Methods 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 description 29
- 239000000047 product Substances 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- 102000016622 Dipeptidyl Peptidase 4 Human genes 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 101000930822 Giardia intestinalis Dipeptidyl-peptidase 4 Proteins 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 1
- 241000486679 Antitype Species 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000007859 condensation product Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005265 energy consumption Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 150000003140 primary amides Chemical class 0.000 description 1
- 239000003223 protective agent Substances 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003335 secondary amines Chemical group 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses a preparation method of a saxagliptin intermediate, which comprises the steps of adding di-tert-butyl dicarbonate and 4-dimethylaminopyridine into amino-protected (S) -3-hydroxyadamantane glycine to perform an activation reaction of carboxylic acid carboxyl, then adding (1S, 3S, 5S) -2-azabicyclo [3.1.0] hexane-3-carbonitrile or salt thereof to form an amide bond, and crystallizing and purifying to obtain a target product of the saxagliptin intermediate. The preparation method provided by the invention has the remarkable advantages of mild reaction conditions, readily available raw materials, simple process, small environmental pollution, low production cost, high production efficiency and the like, and accords with the green chemical concept. The method can be used for preparing the saxagliptin intermediate, and the prepared saxagliptin intermediate is further applied to the production of the saxagliptin.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and relates to a preparation method of an antidiabetic drug intermediate, in particular to a preparation method of a saxagliptin intermediate.
Background
Saxagliptin (saxagliptin), also known as An Lize, chemical name (1S, 3S, 5S) -2- [ (2S) -2-amino-2- (3-hydroxyadamantan-1-yl) acetyl ] -2-azabicyclo [3.1.0] hexane-3-carbonitrile, a novel anti-type 2 diabetes drug commonly developed by Bristol-Myers Squibb and AstraZeneca, belongs to dipeptidyl peptidase IV (DPP-IV) inhibitors, marketed in china 2011.
Saxagliptin has the advantages of obvious hypoglycemic effect, small side effect, good patient compliance, high safety and the like, and has good application and development prospects, so that the research on the synthesis process of important intermediates thereof also draws wide attention in the market. The compound I is an important intermediate for synthesizing saxagliptin, and is directly synthesized into the saxagliptin through an amino deprotection reaction, and the structural formula of the compound I is shown as follows:
in the synthesis of compound I, the carboxyl group of the hydroxyadamantane glycine compound is mainly involved in amide bond formation with the secondary amino group of the cyclopropylpyrrolidine-2-formyl compound, but the carboxylic acid and the organic amine cannot directly form amide, and it is necessary to activate the carboxylic acid or promote the reaction by adding a dehydrating agent. The existing preparation method of the intermediate compound I reported at home and abroad has the defects of longer preparation steps, high cost, serious environmental pollution, non-ideal atomic economy and the like.
Disclosure of Invention
The invention aims to provide a preparation method of a saxagliptin intermediate, which aims to reduce the manufacturing cost of the saxagliptin intermediate, further reduce the production cost of the saxagliptin bulk drug, enhance the market competitiveness and bring greater social benefit.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
a preparation method of a saxagliptin intermediate, which is amino-protected (1S, 3S, 5S) -2- [ (2S) -2-amino-2- (3-hydroxyadamantane-1-yl) acetyl ] -2-azabicyclo [3.1.0] hexane-3-nitrile, and has a chemical structure of a compound I,
wherein PG is a protecting group of amino;
the preparation method comprises the following steps of:
s1, activation reaction of carboxylic acid carboxyl
Dissolving a compound II in an aprotic solvent, and adding di-tert-butyl dicarbonate and 4-Dimethylaminopyridine (DMAP) to perform carboxyl activation reaction to obtain a mixture A;
s2 amide bond formation reaction
Adding a compound III into the mixture A to perform an amide bond formation reaction to obtain a mixture B;
s3, purification of saxagliptin intermediate
Washing the mixture B, adding a drying agent, carrying out suction filtration, reduced pressure distillation, crystallization and suction filtration to finally obtain a target product compound I, namely a target product saxagliptin intermediate;
wherein the compound II is amino-protected (S) -3-hydroxyadamantane glycine, and the structural formula is as follows:
the compound III is (1S, 3S, 5S) -2-azabicyclo [3.1.0] hexane-3-carbonitrile or a salt thereof, and has the structural formula:
wherein PG is a protecting group of amino.
The reaction process of the invention is as follows:
di-tert-butyl dicarbonate is a commonly used amino protecting agent, commonly used in amino acid amino protection. In journal Tetrahydron Letters, volume 36, 39, 1995, in papers Activation of carboxylic acids by, pyrocarbonates. Application of di-tert-butyl pyrocarbonate as condensing reagent in the synthesis of amides of protected amino acids and peptides, pages 7115-7118, it was reported that di-tert-butyl dicarbonate was able to activate carboxylic acid carboxyl groups to convert amino-protected amino acids or peptides into amides, but the kind of the amide obtained by conversion was limited to primary amides having no substituents on the amino groups, i.e. activated carboxylic acids could only react with ammonia or ammonium bicarbonate. This property of di-tert-butyl dicarbonate in this paper is directly applied to the formation of the saxagliptin amide bond, but the corresponding condensation product is not obtained. It is presumed that the amino moiety in the saxagliptin amide group is a secondary amine structure, and that there are two alkyl substituents on the nitrogen atom, and that steric or electrical reasons cause the reaction to be impossible. However, the present application, through optimization of other reagents, uses 4-dimethylaminopyridine as an indirect reaction promoter to obtain ideal results, and the reaction yields an amino-protected saxagliptin intermediate as expected.
As a first limitation of the invention, the mass ratio of the substances of the compound II, the di-tert-butyl dicarbonate, the dimethylaminopyridine and the compound III in the preparation method is 1: 1-2: 1-2: 1 to 2.
As a second limitation of the invention, the protecting group for the amino group is a protecting group including, but not limited to, an alkoxyformyl protecting group, an acyl protecting group or an alkyl protecting group.
As a further definition of the second definition of the invention, the alkoxy formyl protecting group includes tert-butoxy formyl (Boc), benzyloxy formyl (Cbz) or fluorenylmethoxy formyl (Fmoc);
the acyl protecting group comprises phthaloyl (Pht), p-toluenesulfonyl (p-Ts) or trifluoroacetyl (Tfa);
the alkyl protecting group includes benzyl (Bn) or trityl (Trt).
As a third limitation of the present invention, in the step S1, the aprotic solvent is at least one of esters, hydrocarbons, nitriles, or ketones.
As a further limitation to the third limitation of the invention, the esters include methyl acetate, ethyl acetate, butyl acetate; the hydrocarbon comprises dichloromethane and 1, 2-dichloroethane; the nitriles include acetonitrile, propionitrile; the ketone comprises acetone.
As a fourth limitation of the invention, the step S1 and the step S2 are performed at 20 to 30 ℃.
As a fifth limitation of the present invention, the drying agent in the step S3 includes at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, and anhydrous calcium chloride.
As a further limitation to the fifth limitation of the invention, the washing in step S3 is washing with an acid solution, water, an alkali solution, water and saturated brine in this order;
wherein the acid solution comprises at least one of hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid, and the alkali solution comprises at least one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate and potassium carbonate solution; the acid concentration is 0.1-1 mol/L, and the alkali concentration is 0.1-1 mol/L.
As another limitation to the fifth limitation of the present invention, in the step S3, the reduced pressure distillation is performed at a pressure of-0.94 to-0.99 MPa and a temperature of 30 to 50 ℃.
By adopting the technical scheme, compared with the prior art, the invention has the following technical progress:
(1) the preparation method of the saxagliptin intermediate has the remarkable advantages of mild reaction conditions, low-cost and easily-obtained raw materials, simple and convenient process, small environmental pollution, low production cost, high synthesis efficiency and the like;
(2) in the invention, di-tert-butyl dicarbonate and 4-dimethylaminopyridine are used as carboxylic acid activators to activate carboxyl of a compound II, and the associated products generated in the activation reaction process are substances such as tertiary butanol, carbon dioxide and the like which are environment-friendly and easy to treat, so that the method accords with the concept of green chemistry;
(3) the preparation process of the saxagliptin intermediate provided by the invention relates to a novel method for forming an amide bond of the saxagliptin intermediate, and the compound II can directly react with the compound III to generate the compound I after being activated by carboxylic acid carboxyl, so that the preparation process can be effectively simplified, and the production efficiency can be improved; in addition, the reaction is carried out at room temperature without heating or cooling, and the energy consumption is low.
In conclusion, the preparation method of the saxagliptin intermediate provided by the invention has the remarkable advantages of mild reaction conditions, readily available raw materials, simple and convenient process, small environmental pollution, low production cost, high production efficiency and the like, and accords with the green chemistry concept.
The preparation method provided by the invention can be used for preparing the saxagliptin intermediate, and the prepared saxagliptin intermediate can be further applied to the production of the saxagliptin.
Drawings
The invention will be described in more detail below with reference to the accompanying drawings and specific examples.
FIG. 1 shows the nuclear magnetic resonance of Compound I in example 1 of the present invention 1 H NMR spectrum;
FIG. 2 shows the nuclear magnetic resonance of Compound I in example 1 of the present invention 13 C NMR spectrum.
Detailed Description
The invention is further illustrated by the following examples. It should be understood that the described embodiments are only for explaining the present invention and do not limit the present invention.
Materials, reagents, and the like used in the examples of the present invention are commercially available unless otherwise specified. The experimental methods for which specific conditions are not specified in the examples are generally conducted under conventional conditions or under conditions recommended by the manufacturer.
Example 1 preparation method of saxagliptin intermediate
The embodiment is a preparation method of a saxagliptin intermediate, which comprises the following steps in sequence:
s1, activation reaction of carboxylic acid carboxyl
S11, 1000g (namely 3.07 mol) of a compound II (PG=Boc) is taken and dissolved in 10L of aprotic solvent ethyl acetate, 370g (namely 3.07 mol) of dimethylaminopyridine is added, and the mixture is stirred at 25 ℃ until the dimethylaminopyridine is completely dissolved;
s12, dropwise adding 670g (i.e. 3.07 mol) of di-tert-butyl dicarbonate, and stirring at 25 ℃ for reaction for 0.5h to obtain a mixture A.
S2 amide bond formation reaction
S21 330g (i.e. 3.07 mol) of the compound III (1S, 3S, 5S) -2-azabicyclo [3.1.0] hexane-3-carbonitrile are added to the mixture A in three portions;
stirring at S22.25deg.C, monitoring the reaction progress by TLC method, stopping stirring after the reaction is completed to obtain mixture B.
S3, purification of saxagliptin intermediate
S31 mixture B was washed sequentially with the following solutions, see in particular Table 1 below.
Table 1 mixture B washing procedure
S32, adding 500g of anhydrous magnesium sulfate into the washed mixture B, carrying out suction filtration, and carrying out reduced pressure distillation at 50 ℃ under the pressure of-0.95 MPa to remove the solvent to obtain 1050g of a target product saxagliptin intermediate compound I (PG=Boc), wherein the yield of the target product saxagliptin intermediate compound I relative to the yield of the compound II is 82.5%.
Nuclear magnetic resonance of saxagliptin intermediate compound i (pg=boc) 1 The H NMR spectrum is shown in FIG. 1, and the nuclear magnetic spectrum is characterized in that: 1 H-NMR(500MHz,d6-DMSO)0.74-0.76(m,1H),1.03-1.08(m, 1H),1.40(s,9H),1.42-1.65(m,12H),1.88-1.93(m,1H),2.11(m,3H),2.20(dd,1H),2.51-2.53(m,1H),3.87(s,1H),4.34(d,1H),4.42(s,1H),5.14(d,1H),6.86(d, 1H).
nuclear magnetic resonance of saxagliptin intermediate compound i (pg=boc) 13 The C NMR spectrum is shown in FIG. 2, and the nuclear magnetic spectrum is characterized in that: 13 C-NMR(125MHz,d6-DMSO)13.97,17.82,28.67,30.19, 30.22,30.60,35.71,37.15,37.80,38.14,44.88,45.01,45.67,46.62,59.54,67.08,78.77,120.61,156.21,169.95。
examples 2-8 preparation of saxagliptin intermediates
Examples 2-8 are preparation methods of saxagliptin intermediates, and the steps are basically the same as those of example 1, except that the raw material amount and the process parameters are different, the raw material types and the amounts of the different examples are shown in table 2 in detail, and the process parameters in the different preparation steps are shown in table 3.
Table 2 raw material usage amount table in examples 2 to 8
Table 3 table of process parameters in the different preparation steps in examples 2 to 8
Examples 2-8 give a summary of the yields of the desired product saxagliptin intermediate compound I relative to compound ii as shown in table 4.
TABLE 4 summary of target product yields
The experimental result shows that the method can conveniently obtain the target product saxagliptin intermediate compound I with higher and stable yield, and simultaneously has the remarkable advantages of mild reaction conditions, easily available raw materials, simple process, small environmental pollution, low production cost, high production efficiency and the like, and accords with the green chemistry concept.
It is to be understood that the above examples of the present invention are provided by way of illustration only and not by way of limitation of the embodiments of the present invention. Other variations or modifications of the above teachings will be apparent to those of ordinary skill in the art. Not all embodiments are exhaustive. All obvious changes or modifications which come within the spirit of the invention are desired to be protected.
Claims (8)
1. A preparation method of a saxagliptin intermediate, which is characterized in that the saxagliptin intermediate is amino-protected (1S, 3S, 5S) -2- [ (2S) -2-amino-2- (3-hydroxyadamantan-1-yl) acetyl ] -2-azabicyclo [3.1.0] hexane-3-carbonitrile, and has a chemical structure as follows:
wherein PG is a protecting group of amino;
the preparation method comprises the following steps of:
s1, activation reaction of carboxylic acid carboxyl
Dissolving a compound II in an aprotic solvent, and adding di-tert-butyl dicarbonate and 4-dimethylaminopyridine to perform an activation reaction of carboxylic acid carboxyl to obtain a mixture A;
s2 amide bond formation reaction
Adding a compound III into the mixture A to perform an amide bond formation reaction to obtain a mixture B;
s3, purification of saxagliptin intermediate
Washing the mixture B, adding a drying agent, carrying out suction filtration, carrying out reduced pressure distillation, crystallization and suction filtration to finally obtain a target product compound I, namely the saxagliptin intermediate;
wherein the compound II is amino-protected (S) -3-hydroxyadamantane glycine, and the structural formula is as follows:
the compound III is (1S, 3S, 5S) -2-azabicyclo [3.1.0] hexane-3-carbonitrile or a salt thereof, and has the structural formula:
wherein PG is a protecting group of amino.
2. The preparation method of the saxagliptin intermediate according to claim 1, wherein the mass ratio of the substances of the compound II, the di-tert-butyl dicarbonate, the 4-dimethylaminopyridine and the compound III is 1: 1-2: 1-2: 1 to 2.
3. A process for the preparation of a saxagliptin intermediate according to claim 1, characterized in that the protecting group of the amino group comprises tert-butoxyformyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, phthaloyl, p-toluenesulfonyl, trifluoroacetyl, benzyl or trityl.
4. A process for the preparation of a saxagliptin intermediate according to any one of claims 1 to 3, characterized in that in step S1 the aprotic solvent is at least one of esters, hydrocarbons, nitriles or ketones.
5. A process for the preparation of a saxagliptin intermediate according to claim 4, characterized in that,
the esters include methyl acetate, ethyl acetate, butyl acetate;
the hydrocarbon comprises dichloromethane and 1, 2-dichloroethane;
the nitriles include acetonitrile, propionitrile;
the ketone comprises acetone.
6. A process for the preparation of a saxagliptin intermediate according to any one of claims 1 to 3, characterized in that step S1 and step S2 are carried out at 20 to 30 ℃.
7. A process for the preparation of a saxagliptin intermediate according to any one of claims 1 to 3, characterized in that the drying agent in step S3 comprises at least one of anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride.
8. The method for preparing a saxagliptin intermediate according to claim 7, wherein the washing in the step S3 is sequentially washing with an acid solution, water, an alkali solution, water and saturated saline solution;
wherein the acid solution comprises at least one of hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid, and the alkali solution comprises at least one of sodium hydroxide solution, potassium hydroxide solution, sodium carbonate and potassium carbonate solution; the concentration of the acid is 0.1-1 mol/L, and the concentration of the alkali solution is 0.1-1 mol/L.
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Condensation of Carboxylic Acids with Non-Nucleophilic N‑Heterocycles and Anilides Using Boc2O;Atsushi Umehara et al.;《The Journal of Organic Chemistry》;第81卷(第22期);11444-11453 * |
孔金玉等著.《有机合成反应及路线设计研究》.中国原子能出版社,2021,(第2021年5月第1版),99-105. * |
无过渡金属催化含氮杂环衍生物的合成研究;廖春书;《中国优秀硕士学位论文全文数据库 工程科技I辑》(第2020年第12期);B014-73 * |
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