CN116730871A - Synthesis method of candesartan intermediate - Google Patents
Synthesis method of candesartan intermediate Download PDFInfo
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- CN116730871A CN116730871A CN202210232064.9A CN202210232064A CN116730871A CN 116730871 A CN116730871 A CN 116730871A CN 202210232064 A CN202210232064 A CN 202210232064A CN 116730871 A CN116730871 A CN 116730871A
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- 239000002053 C09CA06 - Candesartan Substances 0.000 title claims abstract description 18
- 229960000932 candesartan Drugs 0.000 title claims abstract description 18
- SGZAIDDFHDDFJU-UHFFFAOYSA-N candesartan Chemical compound CCOC1=NC2=CC=CC(C(O)=O)=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C1=NN=N[N]1 SGZAIDDFHDDFJU-UHFFFAOYSA-N 0.000 title claims abstract 5
- 238000001308 synthesis method Methods 0.000 title claims description 9
- JJPIVRWTAGQTPQ-UHFFFAOYSA-N 2-amino-3-nitrobenzoic acid Chemical compound NC1=C(C(O)=O)C=CC=C1[N+]([O-])=O JJPIVRWTAGQTPQ-UHFFFAOYSA-N 0.000 claims abstract description 53
- 238000000034 method Methods 0.000 claims abstract description 19
- VTSNJERCWRUZSX-UHFFFAOYSA-N C1=CC(=C(C(=C1)[N+](=O)[O-])N=C=O)C(=O)O Chemical compound C1=CC(=C(C(=C1)[N+](=O)[O-])N=C=O)C(=O)O VTSNJERCWRUZSX-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000012467 final product Substances 0.000 claims abstract description 6
- YWLQSBPRLUBYOR-UHFFFAOYSA-N 2-amino-3-nitrobenzonitrile Chemical compound NC1=C(C#N)C=CC=C1[N+]([O-])=O YWLQSBPRLUBYOR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 22
- 238000006243 chemical reaction Methods 0.000 claims description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- 239000002253 acid Substances 0.000 claims description 14
- 150000002191 fatty alcohols Chemical class 0.000 claims description 14
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 238000006136 alcoholysis reaction Methods 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 238000003786 synthesis reaction Methods 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 239000002994 raw material Substances 0.000 claims description 6
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 claims description 5
- 239000002585 base Substances 0.000 claims description 5
- 238000005886 esterification reaction Methods 0.000 claims description 5
- 230000009471 action Effects 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 230000020477 pH reduction Effects 0.000 claims description 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 4
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 3
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 230000003301 hydrolyzing effect Effects 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- UMPVNDSOFVQHCW-UHFFFAOYSA-M sodium;2-amino-3-nitrobenzoate Chemical compound [Na+].NC1=C(C([O-])=O)C=CC=C1[N+]([O-])=O UMPVNDSOFVQHCW-UHFFFAOYSA-M 0.000 claims description 3
- 238000010189 synthetic method Methods 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 2
- IOCXBXZBNOYTLQ-UHFFFAOYSA-N 3-nitrobenzene-1,2-diamine Chemical compound NC1=CC=CC([N+]([O-])=O)=C1N IOCXBXZBNOYTLQ-UHFFFAOYSA-N 0.000 claims 1
- YHVNSQNDUXHQLH-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-nitrobenzoic acid Chemical compound CC(C)(C)OC(=O)NC1=C(C(O)=O)C=CC=C1[N+]([O-])=O YHVNSQNDUXHQLH-UHFFFAOYSA-N 0.000 abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- GHOSNRCGJFBJIB-UHFFFAOYSA-N Candesartan cilexetil Chemical compound C=12N(CC=3C=CC(=CC=3)C=3C(=CC=CC=3)C3=NNN=N3)C(OCC)=NC2=CC=CC=1C(=O)OC(C)OC(=O)OC1CCCCC1 GHOSNRCGJFBJIB-UHFFFAOYSA-N 0.000 description 14
- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 12
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 239000000203 mixture Substances 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 9
- 239000000463 material Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 9
- 239000012043 crude product Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 7
- MIVXXTKDCKQHCD-UHFFFAOYSA-N ethyl 2-amino-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC([N+]([O-])=O)=C1N MIVXXTKDCKQHCD-UHFFFAOYSA-N 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000003513 alkali Substances 0.000 description 6
- 150000001540 azides Chemical class 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 239000002699 waste material Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 230000021736 acetylation Effects 0.000 description 4
- 238000006640 acetylation reaction Methods 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- -1 2- (N- (tert-butoxycarbonyl) acetamido) -3-nitrobenzoate Chemical compound 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 238000005660 chlorination reaction Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- NYCBXLQKKUBOGV-UHFFFAOYSA-N ethyl 2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-nitrobenzoate Chemical compound CCOC(=O)C1=CC=CC([N+]([O-])=O)=C1NC(=O)OC(C)(C)C NYCBXLQKKUBOGV-UHFFFAOYSA-N 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- HDCLJQZLTMJECA-UHFFFAOYSA-N methyl 2-amino-3-nitrobenzoate Chemical compound COC(=O)C1=CC=CC([N+]([O-])=O)=C1N HDCLJQZLTMJECA-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- YLXNPMSVXYVEHU-UHFFFAOYSA-N 2-acetamido-3-nitrobenzoic acid Chemical compound CC(=O)NC1=C(C(O)=O)C=CC=C1[N+]([O-])=O YLXNPMSVXYVEHU-UHFFFAOYSA-N 0.000 description 1
- KFIRODWJCYBBHY-UHFFFAOYSA-N 3-nitrophthalic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1C(O)=O KFIRODWJCYBBHY-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- 206010067484 Adverse reaction Diseases 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- XKMRRTOUMJRJIA-UHFFFAOYSA-N ammonia nh3 Chemical compound N.N XKMRRTOUMJRJIA-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
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002364 anti-haemorrhagic effect Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229960004349 candesartan cilexetil Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000004880 explosion Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002430 hydrocarbons Chemical group 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000006462 rearrangement reaction Methods 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 230000001603 reducing effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/02—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from isocyanates with formation of carbamate groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/02—Formation of carboxyl groups in compounds containing amino groups, e.g. by oxidation of amino alcohols
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C263/00—Preparation of derivatives of isocyanic acid
- C07C263/10—Preparation of derivatives of isocyanic acid by reaction of amines with carbonyl halides, e.g. with phosgene
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application relates to a method for synthesizing candesartan intermediate 2- ((tert-butoxycarbonyl) amino) -3-nitrobenzoate, which is characterized by comprising the following steps of: a method for sequentially generating intermediate 2-amino-3-nitrobenzoic acid, 2-amino-3-nitrobenzoate and 2-isocyanato-3-nitrobenzoate from 2-amino-3-nitrobenzonitrile to generate a final product.
Description
Technical Field
The application relates to a method for synthesizing a key intermediate 2- ((tert-butoxycarbonyl) amino) -3-nitrobenzoate of candesartan.
Background
Candesartan (Candesartan) is an effective high-selectivity angiotensin II receptor antagonist antihemorrhagic drug, and has the advantages of better blood pressure reducing effect and less adverse reaction compared with an angiotensin converting enzyme inhibitor because of the specificity and selectivity of increasing the blocking of the angiotensin pi receptor level in circulatory system and tissues. The chemical name of the compound is + -2-ethoxy-1- [ [2' - (1H-tetrazol-5-yl) biphenyl-4-yl ] methyl ] -1H-benzimidazole-7-carboxylic acid, and the chemical structural formula of the compound is shown as a compound VI.
Among them, 2- ((tert-butoxycarbonyl) amino) -3-nitrobenzoate (compound I) is a key intermediate for the synthesis of candesartan.
Wherein R is methyl or ethyl.
Regarding the synthesis of candesartan key intermediate compound I, the synthesis routes disclosed in the prior art include an azide route, a direct amide route and an acetylation route.
The azidation route is the currently main stream synthesis route (US 5196444, W02011145100, WO2013186792, WO2020140193A 1), which uses 3-nitrophthalic acid as raw material, and is prepared by esterification, acyl chlorination, azidation and rearrangement reaction, and concretely comprises the following steps:
however, the azide route can generate a large amount of salt-containing and ammonia nitrogen wastewater, is not easy to treat and is not friendly to the environment. And the thionyl chloride is required to be used for acyl chlorination to bring a large amount of three wastes, and the acyl chloride intermediate is required to be subjected to high-risk azide reaction, so that the method has explosion risk, potential safety hazard exists, and the azide reagent is high in price, so that the method is not economical enough.
Furthermore, document JP2001151744A reports a direct amide process synthesis route of compound I, which uses 2-amino-3-nitrobenzoate as a raw material, directly reacts with di-tert-butyl dicarbonate to obtain 2- (N', N-di-tert-butoxycarbonyl) -3-nitrobenzoate, and then removes one tert-butoxycarbonyl to obtain compound I. The method comprises the following steps:
however, the direct amide method route requires two equivalents of di-tert-butyl dicarbonate due to the problem of reactivity, and then one tert-butoxycarbonyl group is removed, so that the route wastes a large amount of di-tert-butyl dicarbonate, brings serious three-waste problems, is not economical and has no commercial value.
Document JP2001151745A, which is an improvement on the basis of JP2001151744A, proposes an acetylation route, wherein 2-amino-3-nitrobenzoate is used as a raw material, and is reacted with acetic anhydride to obtain an acetylated product 2-acetamido-3-nitrobenzoate, and then with di-tert-butyl dicarbonate to obtain 2- (N- (tert-butoxycarbonyl) acetamido) -3-nitrobenzoate, and finally one acetyl group is removed under the action of alkali to obtain a compound I, specifically as follows.
The modified acetylation route based on the direct anhydride method can reduce the dosage of di-tert-butyl dicarbonate to one equivalent, but needs to carry out acetylation protection, and needs to remove the acetyl protecting group after the reaction is finished, thus the operation is very complicated and does not accord with the principle of green chemistry.
Disclosure of Invention
The application provides a new synthetic route of the compound I for solving various defects existing in the prior art. The new synthesis route related by the application does not involve an azide reaction, does not need to use expensive di-tert-butyl dicarbonate, has simple and convenient operation, low production cost and less three wastes, and is environment-friendly.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. For the purposes of the present application, the following terms are defined below.
Those of ordinary skill in the art will understand "about" and vary somewhat in the context in which the term is used. If the use of the term is not clear to one of ordinary skill in the art, the term "about" will mean up to plus or minus 20% of the particular term, given its context.
The term "and/or" when used in connection with two or more selectable items is understood to mean any one of the selectable items or any two or more of the selectable items.
As used herein, the terms "comprises" or "comprising" are intended to include the recited element, integer or step, but not to exclude any other element, integer or step. In this document, the terms "comprises" or "comprising" when used herein, unless otherwise indicated, also encompass the circumstance of consisting of the recited elements, integers or steps. For example, when reference is made to "comprising" or "including" a particular ingredient, it is also intended to encompass mixtures of such particular ingredients.
As used herein, "consisting essentially of … …" means the major components that make up the mixture. If not specified, a content of more than 50% by weight may be referred to as a main component. The main components may be pure or may consist of a mixture of similar structural or chemical properties, as those skilled in the art will recognize that they can generally be classified as such.
Any reference herein to temperature ranges, pH ranges, weight (mass) ranges, molecular weight ranges, percent ranges, and the like, whether expressed using the terms "range" or "ranges," respectively, includes the endpoints indicated, as well as points between the endpoints.
In a first aspect, the present application provides a method for synthesizing candesartan intermediate 2- ((tert-butoxycarbonyl) amino) -3-nitrobenzoate (formula I).
In one or more specific embodiments, the method for synthesizing the candesartan intermediate (formula I) uses 2-amino-3-nitronitrile (formula II) as a raw material to generate a first intermediate 2-amino-3-nitrobenzoate (formula IV) and a second intermediate 2-isocyanato-3-nitrobenzoate (formula V) and then generates a final product candesartan intermediate (formula I);
the method comprises the following specific steps:
(S10) taking 2-amino-3-nitrobenzonitrile (formula II) as a raw material to obtain 2-amino-3-nitrobenzoate (formula IV) through reaction;
(S20) carrying out phosgenation reaction on the 2-amino-3-nitrobenzoate (formula IV) to obtain 2-isocyanato-3-nitrobenzoate (formula V);
(S30) carrying out alcoholysis reaction on 2-isocyanato-3-nitrobenzoate (formula V) to obtain the final product candesartan intermediate (formula I);
r represents a hydrocarbon group; in one or more embodiments, alkyl groups are preferred; further preferably methyl or ethyl.
In one or more embodiments, 2-amino-3-nitrobenzonitrile (formula II) in step (S10) is subjected to an alcoholysis reaction to provide 2-amino-3-nitrobenzoate (formula IV).
In one or more specific embodiments, in the step (S10), 2-amino-3-nitronitrile (formula II) is subjected to an alcoholysis reaction with a fatty alcohol under the catalysis of a first acid to obtain 2-amino-3-nitrobenzoate (formula IV), wherein the fatty alcohol is one or more of methanol, ethanol or other short-chain fatty alcohols; the first acid is preferably an inorganic acid, and more preferably sulfuric acid.
In one or more embodiments, a third intermediate 2-amino-3-nitrobenzoic acid (formula III) may be further formed before forming the intermediate 2-amino-3-nitrobenzoate (formula IV), and the 2-amino-3-nitrobenzonitrile (formula II) in step (S10) is obtained by the following specific steps:
(S11) hydrolyzing the 2-amino-3-nitronitrile (formula II) to obtain 2-amino-3-nitrobenzoic acid (formula III);
(S12) esterifying 2-amino-3-nitrobenzoic acid (formula III) with fatty alcohol to obtain 2-amino-3-nitrobenzoate (formula IV).
In one or more embodiments, 2-amino-3-nitronitrile (formula II) in step (S11) is hydrolyzed to sodium 2-amino-3-nitrobenzoate under the action of a base, and then acidified with a second acid to obtain 2-amino-3-nitrobenzoic acid (formula III). In one or more embodiments, the fatty alcohol is preferably one or more of methanol, ethanol or other short chain fatty alcohols. In one or more embodiments, the base is preferably an alkali metal hydroxide, and more preferably one or more of sodium hydroxide and potassium hydroxide; the second acid used for acidification is preferably an inorganic acid, more preferably sulfuric acid.
In one or more embodiments, the 2-amino-3-nitrobenzoic acid (formula III) in step (S12) is esterified with a fatty alcohol under the catalysis of a first acid to provide a 2-amino-3-nitrobenzoate (formula IV). In one or more embodiments, the fatty alcohol is preferably one or more of methanol, ethanol or other short chain fatty alcohols; the first acid is preferably an inorganic acid, and more preferably sulfuric acid.
In one or more embodiments, the phosgenation reagent used in the phosgenation reaction of step (S20) is selected from one or more of phosgene, diphosgene, triphosgene.
In one or more embodiments, the alcohol used in the alcoholysis reaction in step (S30) is t-butanol.
More specifically, in one or more embodiments, a preferred synthetic method for candesartan intermediate 2- ((tert-butoxycarbonyl) amino) -3-nitrobenzoate (formula I) comprises the specific steps of:
(1) Hydrolyzing 2-amino-3-nitronitrile (formula II) to obtain 2-amino-3-nitrobenzoic acid (formula III);
(2) Carrying out esterification reaction on the 2-amino-3-nitrobenzoic acid (formula III) to obtain 2-amino-3-nitrobenzoic acid ester (formula IV);
(3) Phosgenating 2-amino-3-nitrobenzoate (formula IV) to obtain 2-isocyanato-3-nitrobenzoate (formula V);
(4) 2-isocyanato-3-nitrobenzoate (formula V) is subjected to alcoholysis reaction to obtain a compound I;
in the step (1), 2-amino-3-nitronitrile (formula II) is hydrolyzed under the action of alkali (solution), and then acidized to obtain 2-amino-3-nitrobenzoic acid (formula III). The alkali used is alkali metal hydroxide, including one or more of sodium hydroxide and potassium hydroxide, wherein the molar ratio of the alkali to the 2-amino-3-nitronitrile is 1:1-6:1, preferably 1:1.5-1:2; the weight ratio of the water content in the alkali (solution) to the 2-amino-3-nitronitrile is 1:5-1:20, preferably 1:8-1:12; the inorganic strong acid is used for acidification, comprising one or more of hydrochloric acid, sulfuric acid and nitric acid, wherein the molar ratio of the acid to the alkali is 1:0.8-1:2, preferably 1:1.
In step (2), the esterification of 2-amino-3-nitrobenzoic acid (formula III) is carried out with a lower aliphatic alcohol in a solvent using concentrated sulfuric acid as a catalyst. The molar ratio of the concentrated sulfuric acid to the 2-amino-3-nitrobenzoic acid is 1:0.5-1:3, preferably 1:1.5-1:2. The lower aliphatic alcohol is any one of methanol and ethanol. The esterification reaction can use lower aliphatic alcohol as a solvent, and the mass ratio of the lower aliphatic alcohol to the 2-amino-3-nitrobenzoic acid is 3:1-20:1, preferably 4:1-6:1; the mixed organic solvent of lower aliphatic alcohol, other organic solvents and composition can also be used as the solvent, wherein the other organic solvents are nonpolar solvents which are miscible with lower aliphatic alcohol and comprise one or more of toluene, xylene and chlorobenzene, and when the mixed solvent is used, the mass ratio of the 2-amino-3-nitronitrile, the lower aliphatic alcohol and the other organic solvents is 1 (0.5-5): 1-5, preferably 1 (1-1.5): 3-5.
In the step (3), any one or more of phosgene, diphosgene, triphosgene and other phosgenation reagents can be used for carrying out the phosgenation reaction on the 2-amino-3-nitrobenzoate, and the molar ratio of the phosgenation reagent to the 2-amino-3-nitrobenzoate is 1:0.33-1:5. The phosgenation reaction is carried out in an inert solvent, wherein the inert solvent is selected from one or more of chlorobenzene, toluene, xylene, ethyl acetate, chloroform and methylene dichloride, and the kind ratio of the inert solvent to the 2-amino-3-nitrobenzoate is 2:1-10:1. The reaction temperature is 25-125 ℃.
In the step (4), the 2-isocyanato-3-nitrobenzoate (formula V) and the alcoholysis reaction are carried out by using tertiary butanol, wherein the molar ratio of the tertiary butanol to the 2-isocyanato-3-nitrobenzoate is 1:1-1:10, preferably 1:2-1:3.
The process flow of the method is as follows:
the synthesis method of the candesartan cilexetil intermediate provided by the application has the following advantages:
1. the heat release and the air release in the reaction process are controllable, the operation is safe, and the method is suitable for large-scale production;
2. the used organic solvent can be recycled, the production cost is low, the three wastes are less, and the environment is protected.
3. Less side reaction, easy purification of the product and high purity of the obtained product.
Detailed Description
The application is further illustrated below with reference to specific examples.
The application provides a synthetic method of candesartan intermediate (formula I): starting from 2-amino-3-nitronitronitrile (formula II), the intermediate 2-amino-3-nitrobenzoic acid (formula III), 2-amino-3-nitrobenzoate (formula IV) and 2-isocyanato-3-nitrobenzoate (formula V) are formed in sequence to form the final product candesartan intermediate (formula I).
Example 1: preparation of 2-amino-3-nitrobenzoic acid
16.3g of 2-amino-3-nitronitrile, 115g of deionized water and 6.0g of sodium hydroxide are added into a four-necked flask, the temperature is raised to reflux after the material is added, the temperature is kept for 4 hours, 18.2g of 30% HCl is added after the material is converted, the mixture is neutralized to neutrality, a large amount of solids are separated out, the mixture is filtered, and a filter cake is dried to obtain 17.1g of yellow solid 2-amino-3-nitrobenzoic acid, wherein the yield is 94.0%.
Example 2: preparation of 2-amino-3-nitrobenzoic acid
16.3g of 2-amino-3-nitronitrile, 150g of deionized water and 11.2g of potassium hydroxide are added into a four-necked flask, the temperature is raised to reflux after the material is added, the temperature is kept for 2 hours, 24.3g of 30% HCl is added after the material is converted, the mixture is neutralized to neutrality, a large amount of solids are separated out, the mixture is filtered, and a filter cake is dried to obtain 17.3g of 2-amino-3-nitrobenzoic acid, so that the yield is 95.1%.
Example 3: preparation of 2-amino-3-nitrobenzoic acid
16.3g of 2-amino-3-nitronitrile, 32.6g of deionized water and 48.9g of concentrated sulfuric acid are added into a four-necked flask, the mixture is heated to reflux after being fed, and the mixture is cooled to room temperature after being kept for 12 hours. After the reaction is finished, 50g of water is added for dilution, a large amount of solids are separated out, and a yellow crude product is obtained by filtration. The crude product was dried and recrystallized from ethyl acetate to give 12.2g of pure 2-amino-3-nitrobenzoic acid in 67.2% yield.
Example 4: preparation of methyl 2-amino-3-nitrobenzoate
9.1g of 2-amino-3-nitrobenzoic acid, 45.5g of anhydrous methanol and 18.2g of concentrated sulfuric acid are added into a four-necked flask, the temperature is raised to reflux after the material is added, the temperature is kept for 8 hours, the temperature is reduced to room temperature, and the filtration is carried out, so that 7.4g of 2-amino-3-nitrobenzoic acid methyl ester is obtained, the yield is 70.5%, and the purity is 99%.
Example 5: preparation of ethyl 2-amino-3-nitrobenzoate
16.3g of 2-amino-3-nitronitrile, 81.5g of absolute ethyl alcohol and 19.6g of concentrated sulfuric acid are added into a four-necked flask, the temperature is raised to reflux after the material is added, and the reaction is stopped after the temperature is kept for 5 hours. The reaction was cooled to room temperature, a large amount of yellow solid was precipitated, and the crude product was obtained by filtration, and then the crude product was recrystallized with ethanol to obtain 12.9g of ethyl 2-amino-3-nitrobenzoate as a pure product, with a yield of 61.3% and a purity of 99%.
Example 6: preparation of ethyl 2-amino-3-nitrobenzoate
17.1g of 2-amino-3-nitrobenzoic acid, 17.1g of absolute ethyl alcohol, 80g of toluene and 34.2g of concentrated sulfuric acid are added into a four-necked flask, the temperature is raised to reflux after the material is added, and the reaction is stopped after the temperature is kept for 5 hours. Separating the solution while the solution is hot, concentrating and drying the upper organic layer to obtain crude 2-amino-3-ethyl nitrobenzoate, and crystallizing the crude 2-amino-3-ethyl nitrobenzoate with ethanol to obtain pure product 14.9 g, with 75.6% yield and 99% purity.
Example 7: preparation of ethyl 2-amino-3-nitrobenzoate
17.1g of the obtained 2-amino-3-nitrobenzoic acid, 17.1g of absolute ethyl alcohol, 80g of toluene and 34.2g of concentrated sulfuric acid are added into a four-necked flask, the temperature is raised to 90 ℃ after the material feeding is finished, and the reaction is stopped after the temperature is kept for 20 hours. Separating the solution while the solution is hot, concentrating and drying the toluene layer at the upper layer to obtain crude 2-amino-3-ethyl nitrobenzoate, and crystallizing the crude 2-amino-3-ethyl nitrobenzoate with ethanol to obtain 15.3g of pure 2-amino-3-ethyl nitrobenzoate with the yield of 77.6 percent and the purity of 99 percent.
Example 8: preparation of ethyl 2-amino-3-nitrobenzoate
17.1g of the obtained 2-amino-3-nitrobenzoic acid, 17.1g of absolute ethyl alcohol, 80. 80g g of chlorobenzene and 25.7g of concentrated sulfuric acid are added into a four-necked flask, the temperature is raised to reflux after the material addition is finished, and the reaction is stopped after the temperature is kept for 4 hours. Separating the solution while the solution is hot, concentrating and drying the upper organic layer to obtain crude 2-amino-3-ethyl nitrobenzoate, and crystallizing the crude 2-amino-3-ethyl nitrobenzoate with ethanol to obtain 15.1g of pure 2-amino-3-ethyl nitrobenzoate with the yield of 76.6% and the purity of 99%.
Example 9: preparation of ethyl 2- ((tert-butoxycarbonyl) amino) -3-nitrobenzoate
1.48g of triphosgene, 10g of chlorobenzene, 2.1g of ethyl 2-amino-3-nitrobenzoate, 0.1g of triethylamine and 30g of chlorobenzene are added into a three-necked flask, and slowly dropwise added into the three-necked flask at room temperature, wherein white smoke is generated in the dropwise adding process. After the dripping is finished, the temperature of the system is increased to 80 ℃, and the temperature is kept for 2 hours.
After the completion of the reaction, the solvent was removed by rotary evaporation, and 10g of t-butanol was added thereto, followed by refluxing at elevated temperature for 1 hour. Cooling after the reaction is finished, and removing tertiary butanol by rotary evaporation to obtain a crude product. The crude product is crystallized by normal hexane to obtain pale yellow powder with the yield of 64 percent and the purity of 99.1 percent.
Example 10: preparation of ethyl 2- ((tert-butoxycarbonyl) amino) -3-nitrobenzoate
To a three-necked flask, ethyl 2-amino-3-nitrobenzoate (2.1 g,10 mmol), toluene (10.5 g) was charged, the temperature was raised to 80℃and phosgene was introduced, after HPLC monitoring until the starting material disappeared, the introduction of light was stopped and nitrogen was bubbled to remove excess phosgene.
The solvent was removed by rotary evaporation, and then 10g of t-butanol was added thereto, followed by reflux at elevated temperature for 1 hour. Cooling after the reaction is finished, and removing tertiary butanol by rotary evaporation to obtain a crude product. The crude product is crystallized by normal hexane to obtain pale yellow powder with the yield of 92 percent and the purity of 99.3 percent.
The above-described embodiments are merely examples for clearly illustrating the application and are not intended to limit the application in any way. It will be apparent to those skilled in the art from this disclosure that various other changes and modifications can be made, and equivalents of the application as defined in the claims appended hereto are intended to be applicable to other conventional alternatives having similar needs.
Claims (10)
1. A method for synthesizing candesartan intermediate (formula I), which is characterized by comprising the following steps: starting from 2-amino-3-nitronitrile (formula II) to form a first intermediate 2-amino-3-nitrobenzoate (formula IV) and a second intermediate 2-isocyanato-3-nitrobenzoate (formula V) to form a final product candesartan intermediate (formula I);
the method comprises the following specific steps:
(S10) taking 2-amino-3-nitrobenzonitrile (formula II) as a raw material to obtain 2-amino-3-nitrobenzoate (formula IV) through reaction;
(S20) carrying out phosgenation reaction on the 2-amino-3-nitrobenzoate (formula IV) to obtain 2-isocyanato-3-nitrobenzoate (formula V);
(S30) carrying out alcoholysis reaction on 2-isocyanato-3-nitrobenzoate (formula V) to obtain the final product candesartan intermediate (formula I);
wherein R represents methyl or ethyl.
2. The synthesis method according to claim 1, wherein in the step (S10), 2-amino-3-nitronitrile (formula II) is subjected to an alcoholysis reaction to obtain 2-amino-3-nitrobenzoate (formula IV).
3. The synthesis method according to claim 2, wherein in the step (S10), 2-amino-3-nitronitrile (formula II) is subjected to an alcoholysis reaction with a fatty alcohol under the catalysis of a first acid to obtain 2-amino-3-nitrobenzoate (formula IV), wherein the fatty alcohol is one or more selected from methanol and ethanol; the first acid is sulfuric acid.
4. The synthesis according to claim 1, characterized in that a third intermediate 2-amino-3-nitrobenzoic acid (formula III) is further produced before the intermediate 2-amino-3-nitrobenzoate (formula IV); in the step (S10), 2-amino-3-nitronitrile (formula II) is obtained by the following specific steps:
(S11) hydrolyzing the 2-amino-3-nitronitrile (formula II) to obtain 2-amino-3-nitrobenzoic acid (formula III);
(S12) esterifying 2-amino-3-nitrobenzoic acid (formula III) with fatty alcohol to obtain 2-amino-3-nitrobenzoate (formula IV).
5. The synthesis method according to claim 4, wherein in the step (S11), 2-amino-3-nitroaniline (formula II) is hydrolyzed into sodium 2-amino-3-nitrobenzoate under the action of a base, and then the sodium 2-amino-3-nitrobenzoate is obtained by acidification with a second acid.
6. The synthesis method according to claim 5, wherein the base is an alkali metal hydroxide selected from one or more of sodium hydroxide and potassium hydroxide; the second acid used for acidification is an inorganic acid.
7. The synthesis method according to claim 4, wherein in the step (S12), 2-amino-3-nitrobenzoic acid (formula III) is subjected to esterification reaction with fatty alcohol under the catalysis of a first acid to obtain 2-amino-3-nitrobenzoate (formula IV), wherein the fatty alcohol is one or more selected from methanol and ethanol; the first acid is sulfuric acid.
8. The synthetic method according to claim 1, wherein in the step (S20), the phosgenation reagent used for the phosgenation reaction is one or more selected from the group consisting of phosgene, diphosgene and triphosgene.
9. The method according to claim 1, wherein in the step (S30), the alcohol used in the alcoholysis reaction is t-butanol.
10. The synthesis method according to claim 6, wherein in the step (S11), the molar ratio of the base to 2-amino-3-nitronitrile (formula II) is 1:1 to 6:1; in the step (S12), concentrated sulfuric acid is used as a catalyst, and the molar ratio of the concentrated sulfuric acid to the 2-amino-3-nitrobenzoic acid (formula III) is 1:0.5-1:3; the molar ratio of the phosgenation reagent to the 2-amino-3-nitrobenzoate (formula IV) in step (S20) is 1:0.33 to 1:5; the molar ratio of the tertiary butanol to the 2-isocyanato-3-nitrobenzoate (formula V) in the step (S30) is 1:1-1:10.
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