CN106977415B - Intermediate of shakubiqu and preparation method thereof - Google Patents

Intermediate of shakubiqu and preparation method thereof Download PDF

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CN106977415B
CN106977415B CN201710014972.XA CN201710014972A CN106977415B CN 106977415 B CN106977415 B CN 106977415B CN 201710014972 A CN201710014972 A CN 201710014972A CN 106977415 B CN106977415 B CN 106977415B
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CN106977415A (en
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孙国栋
陈磊
韩小东
李顺
曾洁滨
王仲清
罗忠华
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Guangdong HEC Pharmaceutical
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Sunshine Lake Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/65—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by splitting-off hydrogen atoms or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/32—Decarboxylation
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C07F7/1872—Preparation; Treatments not provided for in C07F7/20
    • C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888

Abstract

The invention relates to a shakubitqu intermediate and a preparation method thereof, wherein the shakubitqu intermediate is a compound shown as a formula (04) and can be prepared by carrying out deprotection reaction on the compound shown as a formula (03). Furthermore, the invention also provides a method for preparing the shakubitrex by using the compound shown as the formula (04) as an intermediate. The method has the advantages of easily available raw materials, simple process, economy, environmental protection and the like, and is very suitable for industrial production.

Description

Intermediate of shakubiqu and preparation method thereof
Technical Field
The invention relates to the field of pharmaceutical chemicals, and particularly relates to a shakubiqu intermediate and a preparation method thereof.
Background
Sabotabiqu (Sacubitril), chemically known as 4- (((2S,4R) -1- ([1,1' -biphenyl ] -4-yl) -5-ethoxy-4-methyl-5-oxopentan-2-yl) amino) -4-oxobutanoic acid, having the following structural formula:
Figure BDA0001205488580000011
in 7 months 2015, the us FDA approved marketed anti-heart failure drug Entresto, which is a combination of the angiotensin II inhibitor valsartan and the enkephalinase inhibitor sabotabifril (Sacubitril). Valsartan can improve vasodilatation and stimulate the body to excrete sodium and water, while sabotabifonazole can block the action mechanism of 2 polypeptides threatening to reduce blood pressure, so that the valsartan is called as a dual inhibitor of angiotensin II receptors and enkephalinase; the Chinese medicinal composition clinically shows a unique action mode, and has the effects of lowering blood pressure and reducing heart failure better than that of standard medicaments.
The prior art discloses a preparation method of a plurality of shakubiqus, which comprises the following steps:
WO2008031567a1 discloses a method for preparing biphenyl butyric acid or derivatives thereof with substituted 4-amino group and application thereof in preparation of enkephalinase inhibitor, and the document discloses a method for preparing biphenyl butyric acid or derivatives thereof with substituted 4-amino group by using biphenyl propanol with substituted 2-amino group as a starting material, oxidizing into aldehyde and Witting to obtain biphenyl crotonic acid or derivatives thereof with substituted 4-amino group, and then performing reduction and reaction and chiral resolution in the presence of hydrogen and transition metal elements of groups 7, 8 and 9 in the periodic table of chemical elements as a catalyst and chiral ligand to prepare biphenyl butyric acid or derivatives thereof with substituted 4-amino group. The biphenyl butyric acid or the derivative thereof with the amino substituted at the 4-position can be further used for preparing enkephalinase inhibitors, including shakubitrex. An exemplary reaction is as follows:
Figure BDA0001205488580000012
WO2008083967A2 discloses a method for preparing Sacubitril by using 2-carbonyl proline as a raw material and carrying out reactions such as carboxyl activation, biphenyl substitution, carbonyl reduction, chiral methylation, ring-opening reaction, amidation condensation and the like. The reaction is as follows:
Figure BDA0001205488580000021
although the synthetic routes disclosed in WO2008031567a1 and WO2008083967a2 have certain differences in the use of starting materials, the method of forming chirality, and the order of unit reactions, they have disadvantages that chiral materials are difficult to obtain, reaction steps are numerous, chiral catalytic reduction catalysts are expensive, and protection and deprotection of carboxyl groups or amino groups are repeated, and thus it is difficult to successfully realize industrialization.
CN104557600A is prepared by reacting a chiral induction reagent (S) -1- (alpha-aminobenzyl) -2-naphthol (S-betti Base) and 2R-methyl-4-oxo-butyric acid through the steps of cyclization, addition, debenzylation, ring opening, esterification, amidation and the like. The reaction formula is as follows:
Figure BDA0001205488580000022
the process method for preparing the shakubiqu has the advantages of difficult obtainment of raw materials and more complicated reaction.
Disclosure of Invention
Summary of The Invention
Compared with the prior art, the invention provides another preparation method of the shakubiqu suitable for industrial production.
The method for preparing the shakubiqu adopts the compound shown as the formula (04) as a starting material to prepare the shakubiqu,
Figure BDA0001205488580000031
wherein the content of the first and second substances,
said R1Can be phenyl, methoxy, hydroxyl, chlorine, bromine, iodine, methanesulfonic acid (OMs), trifluoromethanesulfonic acid (OTf) or p-toluenesulfonic acid (OTs);
said R2Can be
Figure BDA0001205488580000032
Wherein R is3May be hydrogen, - (C)1-C4) Alkyl or- (C)1-C4) Alkyl-aryl groups. Wherein said is- (C)1-C4) The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl in some embodiments. Wherein said is- (C)1-C4) Alkyl-aryl may in some embodiments be benzyl or optionally substituted benzyl.
Wherein R is4May be hydrogen, - (C)1-C4) Alkyl, - (C)3-C6) Heterocyclyl, - (C)1-C4) Alkyl-aryl, trimethylsilyl, triethylsilyl or tert-butyldimethylsilyl. Wherein said is- (C)1-C4) The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl in some embodiments. Wherein said is- (C)1-C4) Alkyl-aryl may in some embodiments be benzyl or optionally substituted benzyl.
The method for preparing the shakubiqu provided by the invention has the advantages of easily available raw materials, simple process, economy, environmental protection and the like.
In a first aspect, the invention provides a starting material for preparing shakubitqu, a compound shown as a formula (04); and a process for producing the compound represented by the formula (04).
In a second aspect, the present invention provides a process for preparing shakubitrex using a compound represented by formula (04) as a starting material.
Definition of terms
The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
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 to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of elements, and the 75 th version of the handbook of chemistry and Physics, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "-C1-C6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl", as used herein, denotes a saturated, straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms, wherein the alkyl radical may be optionally substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or tricyclic ring containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, heterocyclyl may be carbon-or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranA group selected from the group consisting of dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxepinyl, thiacycloheptyl, oxazepanyl
Figure BDA0001205488580000041
Radical, diaza
Figure BDA0001205488580000042
Radical, S-N-aza
Figure BDA0001205488580000043
Radicals, indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
In some embodiments, heterocyclyl is a 3-6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 3 to 6 atoms may be carbon-based or nitrogen-based, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 3 to 6 atoms include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl,dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Said heterocyclyl group of 3 to 6 atoms may be optionally substituted by one or more substituents as described herein.
In some embodiments, heterocyclyl is a 4-7 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4-7 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 4 to 7 atoms may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 to 7 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxacycloheptanyl, oxazepanyl, thiazepanyl, thiazepan
Figure BDA0001205488580000051
Radical, diaza
Figure BDA0001205488580000052
Radical, S-N-aza
Figure BDA0001205488580000053
And (4) a base. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. Said heterocyclyl group of 4 to 7 atoms may be optionally substituted by one or more substituents as described herein.
In another embodiment, heterocyclyl is a 4-atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 4 ring atoms in which at least one ring atom is substituted by a member selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group consisting of 4 atoms may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 4 atoms include, but are not limited to: azetidinyl, oxetanyl, thietanyl. The 4-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In another embodiment, heterocyclyl is a 5 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 5 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a 5-atom heterocyclic group may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of 5-atom heterocyclic groups include, but are not limited to: pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group. The 5-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In another embodiment, heterocyclyl is a 6 atom heterocyclyl and refers to a saturated or partially unsaturated monocyclic ring containing 6 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Unless otherwise specified, a heterocyclic group of 6 atoms may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 6 atoms include, but are not limited to: tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl. In heterocyclic radicals of-CH2Examples of-groups substituted with-C (O) -include, but are not limited to, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, 1, 1-dioxothiomorpholinyl. The 6-atom heterocyclyl group may be optionally substituted with one or more substituents described herein.
In yet another embodiment, heterocyclyl is a 7-12 atom heterocyclyl and refers to a saturated or partially unsaturated spiro-or fused-bicyclic ring containing 7-12 ring atoms in which at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen atoms. Unless otherwise specified, a heterocyclic group of 7 to 12 atoms may be carbon-based or nitrogen-based, and-CH2The group may optionally be replaced by-c (o) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of heterocyclic groups consisting of 7 to 12 atoms include, but are not limited to: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1, 3-benzodioxolyl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. Said heterocyclyl group consisting of 7 to 12 atoms may optionally be substituted by one or more substituentsSubstituted by the substituents described in the invention.
The terms "fused bicyclic ring," "fused bicyclic group," and "fused ring group" are used interchangeably herein and all refer to a monovalent or multivalent saturated or partially unsaturated bridged ring system, which refers to a non-aromatic bicyclic ring system. Such systems may contain independent or conjugated unsaturated systems, but the core structure does not contain aromatic or heteroaromatic rings (although aromatic groups may be substituted thereon).
The terms "spirocyclic", "spiro", "spirobicyclic" or "spirobicyclic" are used interchangeably herein to refer to a monovalent or multivalent saturated or partially unsaturated ring system in which one ring is derived from a specific ring carbon atom on another ring. For example, as described below, one saturated bridged ring system (rings B and B') is referred to as "fused bicyclic ring", while ring a and ring B share one carbon atom in two saturated ring systems, referred to as "spiro" or "spirobicyclic ring". Each ring in the fused bicyclic and spirobicyclic groups may be a carbocyclic or heterocyclic group, and each ring is optionally substituted with one or more substituents described herein.
Figure BDA0001205488580000061
The term "unsaturated" as used herein means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "aryl" denotes monocyclic, bicyclic and tricyclic carbon ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, wherein each ring system comprises a ring of 3 to 7 atoms with one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of the aryl group may include phenyl, naphthyl, and anthracene. The aryl group may independently be optionally substituted with one or more substituents described herein.
Detailed Description
In a first aspect, the invention provides a starting material for preparing shakubitqu, a compound shown as a formula (04); and a process for producing the compound of the formula (04).
In some embodiments, the compounds of the present invention are of formula (04), wherein R is1Is phenyl.
In some embodiments, the compounds of the present invention are of formula (04), wherein R is2is-COOH, -COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOC(CH3)3、-COOCH2Ph、-CH2OH、-CH2O CH3、-CH2O CH2CH3、-CH2O CH(CH3)2、-CH2O C(CH3)3、-CH2O CH2Ph、-CH2O C(Ph)3、-CH2O Si(CH3)3、-CH2O Si(CH2CH3)3、-CH2O Si(CH3)2C(CH3)3、-CONH2、-CONHCH3、-CONHCH2CH3、-CONHCH(CH3)2、-CONHC(CH3)3、-CONHCH2Ph or
Figure BDA0001205488580000071
In some embodiments, the compound of formula (04) may be a structure having one of the following:
Figure BDA0001205488580000072
Figure BDA0001205488580000081
Figure BDA0001205488580000091
the preparation method of the compound shown in the formula (04) can comprise the steps of preparing the compound shown in the formula (04) through deprotection reaction of the compound shown in the formula (03),
Figure BDA0001205488580000092
wherein the content of the first and second substances,
said R1And R2May be a group as described previously;
said R5May be hydrogen, - (C)1-C4) Alkyl or- (C)1-C4) Alkyl-aryl groups. Wherein said is- (C)1-C4) The alkyl group may be methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl in some embodiments. Wherein said is- (C)1-C4) Alkyl-aryl may in some embodiments be benzyl or optionally substituted benzyl.
The compound shown in the formula (03) can be prepared by introducing a chiral methyl group through a substitution reaction of the compound shown in the formula (01) and the compound shown in the formula (02),
Figure BDA0001205488580000093
wherein the content of the first and second substances,
said R1、R2And R5May be a group as described in the foregoing,
said R6Can be trifluoromethanesulfonic acid (OTf), methanesulfonic acid (OMs) or p-toluenesulfonic acid (O)Ts)。
The compound shown in the formula (01) can be prepared by taking the compound shown in the formula (00) as a starting material and carrying out condensation reaction,
Figure BDA0001205488580000101
wherein R is1May be a group as described above.
In some embodiments, the present invention provides a method of preparing a compound of formula (04),
Figure BDA0001205488580000102
wherein R is1And R2May be a group as described hereinbefore, comprising the steps of:
a) the compound shown in the formula (01) and the compound shown in the formula (02) are subjected to substitution reaction to introduce chiral methyl,
Figure BDA0001205488580000103
the compound shown as the formula (03) is obtained,
Figure BDA0001205488580000104
wherein the content of the first and second substances,
said R1、R2、R5And R6May be a group as described previously;
b) the compound shown in the formula (03) is subjected to deprotection reaction to prepare the compound shown in the formula (04). In some embodiments, the method of preparing a compound of formula (04) according to the present invention comprises the steps of,
Figure BDA0001205488580000105
wherein R is1And R2May be a group as described in the foregoing,
a) taking a compound shown in a formula (00) as a starting material, and preparing a compound shown in a formula (01) through a condensation reaction;
Figure BDA0001205488580000106
wherein the content of the first and second substances,
said R1And R5May be a group as described previously;
b) carrying out substitution reaction on the compound shown in the formula (01) and the compound shown in the formula (02) to introduce chiral methyl to prepare the compound shown in the formula (03),
Figure BDA0001205488580000111
wherein the content of the first and second substances,
said R1、R2、R5And R6May be a group as described previously;
c) the compound shown in the formula (03) is subjected to deprotection reaction to prepare the compound shown in the formula (04).
In some embodiments, the method of preparing a compound of formula (04) according to the present invention comprises the steps of,
Figure BDA0001205488580000112
wherein R is1Is a phenyl group, and the phenyl group,
the R is2Is that
Figure BDA0001205488580000113
Wherein R is3Can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,Tert-butyl or benzyl, wherein R is4Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl, tetrahydropyranyl;
a) taking a compound shown in a formula (00) as a starting material, and carrying out a condensation reaction under an alkaline condition to prepare a compound shown in a formula (01);
Figure BDA0001205488580000114
wherein the content of the first and second substances,
said R1Is phenyl;
said R5Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl;
b) carrying out substitution reaction on the compound shown in the formula (01) and the compound shown in the formula (02) under a strong alkali condition to introduce chiral methyl to prepare the compound shown in the formula (03),
Figure BDA0001205488580000115
wherein the content of the first and second substances,
said R1Is a phenyl group, and the phenyl group,
the R is2Is that
Figure BDA0001205488580000121
Wherein R is3Can be hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl, wherein R is4Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl, trimethylsilyl, triethylsilyl or tert-butyldimethylsilyl;
the R is5Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl,
the R is6Is trifluoromethanesulfonic acid (OTf), formazanSulfonic acid groups (OMs) or p-toluenesulfonate groups (OTs);
c) the compound shown in the formula (03) is reacted in the presence of acid or alkali, and the compound shown in the formula (04) is prepared through deprotection reaction.
In some embodiments, the present invention provides a method for preparing a compound of formula (01), comprising: taking a compound shown in a formula (00) as a starting material, carrying out a condensation reaction with N, N' -carbonyldiimidazole and a compound shown in a formula (07) in the presence of magnesium chloride and triethylamine to obtain a compound shown in a formula (01),
Figure BDA0001205488580000122
wherein said R5Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or benzyl.
In some embodiments, the compound represented by formula (01) is prepared by using the compound represented by formula (00) as a starting material, and reacting with Meldrum's acid, 4-dimethylaminopyridine and R in the presence of N, N-diisopropylethylamine5OH and pivaloyl chloride are subjected to condensation reaction to obtain the compound shown in the formula (01).
In some embodiments, the compound of formula (00) of the present invention is 4-biphenylacetic acid.
In some embodiments, the method of preparing a compound of formula (03) according to the present invention comprises: and (2) carrying out substitution reaction on the compound shown in the formula (01) and the compound shown in the formula (02) in the presence of strong alkali, and introducing a chiral methyl group to obtain the compound shown in the formula (03). In some embodiments the strong base is sodium hydride.
In some embodiments, the method of preparing a compound of formula (04) according to the present invention comprises: the compound shown in the formula (03) is subjected to deprotection reaction in the presence of acid or alkali to obtain the compound shown in the formula (04). In some embodiments the acid is trifluoroacetic acid. In some embodiments the base is lithium hydroxide.
In some embodiments, the process of the present invention for preparing a compound of formula (04) may be represented by the following general formula:
Figure BDA0001205488580000131
the method for preparing the compound of formula (04) or the intermediate thereof according to the present invention can be implemented by those skilled in the art, based on the disclosure, and the reaction conditions can be appropriately adjusted according to the circumstances, such as selecting other appropriate reaction solvents, adjusting the reaction temperature, and appropriately prolonging the reaction time to obtain better reaction effect. The compound represented by the formula (04) described in the present invention can be produced by the above production method of the present invention.
The compound shown as the formula (04) prepared by the preparation method can be used for preparing the shakubiqu.
In a second aspect, the present invention also provides a process for preparing shakubiqu using a compound represented by formula (04) as a starting material,
Figure BDA0001205488580000132
which comprises the following steps:
preparing shakubitrex by using the compound shown in the formula (04),
Figure BDA0001205488580000133
wherein the content of the first and second substances,
said R1Is phenyl, methoxy, hydroxyl, chlorine, bromine, iodine, methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid;
said R2Is that
Figure BDA0001205488580000134
R3Is hydrogen, - (C)1-C4) Alkyl or- (C)1-C4) Alkyl-aryl;
R4is hydrogen, - (C)1-C4) Alkyl, - (C)3-C6) Heterocyclyl, - (C)1-C4) Alkyl-aryl, trimethylsilyl, triethylsilyl or tert-butyldimethyl
And (3) silicon base.
In some embodiments, the sabotabifonazole preparation method has the following general formula:
Figure BDA0001205488580000141
in some embodiments, the method of preparing shakubiqu according to the invention comprises the following steps:
a) the compound shown in the formula (04) is used as a starting material, and the compound shown in the formula (05) is prepared through an enzyme catalytic reaction,
Figure BDA0001205488580000142
wherein the content of the first and second substances,
said R1Can be phenyl, methoxy, hydroxyl, chlorine, bromine, iodine, methanesulfonic acid (OMs), trifluoromethanesulfonic acid (OTf) or p-toluenesulfonic acid (OTs);
said R2Can be
Figure BDA0001205488580000143
Wherein R is3May be hydrogen, - (C)1-C4) Alkyl or- (C)1-C4) Alkyl-aryl, wherein- (C)1-C4) Alkyl groups may be methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl in some embodiments, wherein- (C) is as described1-C4) Alkyl-aryl may be benzyl or optionally substituted benzyl in some embodiments;
wherein R is4May be hydrogen, - (C)1-C4) Alkyl, - (C)3-C6) Heterocyclyl, - (C)1-C4) Alkyl-aryl, trimethylsilyl, triethylsilyl or tert-butyldimethylsilyl, wherein- (C)1-C4) Alkyl groups may be methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl in some embodiments, wherein- (C) is as described1-C4) Alkyl-aryl may be benzyl or optionally substituted benzyl in some embodiments;
b) preparing a compound represented by formula (06) from a compound represented by formula (05),
Figure BDA0001205488580000144
c) the compound shown in the formula (06) and succinic anhydride are subjected to amidation condensation reaction to prepare the shakubiqu.
In some embodiments, the method of preparing shakubiqu according to the invention comprises the following steps:
a) the compound shown in the formula (04) is used as a starting material, and the compound shown in the formula (05) is prepared through an enzyme catalytic reaction,
Figure BDA0001205488580000145
wherein R is1Is benzene, and the benzene is benzene, toluene, xylene, or mixtures thereof,
R2is that
Figure BDA0001205488580000151
Wherein R is3Is hydrogen, - (C)1-C4) Alkyl or- (C)1-C4) Alkyl-aryl groups. Wherein said is- (C)1-C4) Alkyl groups may be methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl in some embodiments, wherein- (C) is as described1-C4) Alkyl-aryl may be benzyl or optionally substituted benzyl in some embodiments;
b) preparing a compound represented by formula (06) from a compound represented by formula (05),
Figure BDA0001205488580000152
c) the compound shown in the formula (06) and succinic anhydride are subjected to amidation condensation reaction to prepare the shakubiqu.
In some embodiments, the method of preparing shakubitril according to the present invention, wherein the enzyme-catalyzed reaction is performed in the presence of ω -transaminase and pyridoxal phosphate.
In some embodiments, the preparation of the compound represented by formula (06) in step b) may be performed by first performing a hydrolysis reaction on the compound represented by formula (05), and then performing an esterification reaction on the compound with ethanol, thereby obtaining the compound represented by formula (06).
In the step c), the compound shown as the formula (06) and succinic anhydride are subjected to amidation condensation reaction in the presence of alkali to obtain the shakubiqu. Such preparation methods are disclosed in the prior art, e.g. in WO2008031567a1 and CN104557600a, and known to the person skilled in the art.
Detailed Description
In order to make the technical solution of the present invention better understood by those skilled in the art, the present invention exemplarily provides a part of preparation examples, and the following further discloses some non-limiting examples to further explain the present invention in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, mol/L and N means mol/L, h means hour, g means g, ml means ml, L means L, DEG C means centigrade, ESI-MS means electrospray ionization mass spectrometry, and TLC means thin layer chromatography.
Example 1
Example 1-a: preparation of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate
Figure BDA0001205488580000153
To a 500mL three-necked flask A, 200mL of ethyl acetate and 28.64g N, N' -carbonyldiimidazole were added at room temperature, and 25.00g of 4-biphenylacetic acid was added in portions to the flask A, and the gas generation rate was controlled. And after the feeding is finished, heating the reaction solution to 45 ℃ for reaction for 3h, cooling to 20-30 ℃, and vacuumizing for 1h under reduced pressure for later use. To a 1L reaction flask B at room temperature were added 280mL of ethyl acetate and 28.06g of EtO2CCH2COOK and 15.70g magnesium chloride (MgCl)2) And controlling the temperature to be 20-30 ℃, slowly dropwise adding 19.07g of Triethylamine (TEA), and continuously stirring for 1h after dropwise adding is finished. And adding the materials in the reaction bottle A into the reaction bottle B at room temperature, heating to 45 ℃, and carrying out heat preservation reaction for 16 hours. And cooling the reaction liquid to 20-30 ℃, slowly dropwise adding 180mL of 4N hydrochloric acid solution, separating the liquid, washing an organic phase with 6.5% sodium bicarbonate solution for three times, wherein the dosage is 250mL each time, collecting the organic phase, and evaporating the solvent at 45 ℃ under reduced pressure to obtain a yellowish-brown oily substance. Adding 150mL of normal hexane into the obtained oily matter, stirring for 18h at 20-30 ℃, filtering, washing a filter cake with the normal hexane, and drying for 5h under vacuum at 40-50 ℃ to obtain 4- ([1,1' -biphenyl)]26.3g of ethyl (4-yl) -3-oxobutanoate, yield 79.1%. 1H NMR (600MHz, CDCl)3)δ7.60(dt,J＝15.9,6.1Hz,4H),7.47(t,J＝7.7Hz,2H),7.37(dt,J＝9.7,7.9Hz,1H),7.33–7.28(m,2H),4.25–4.18(m,2H),3.90(s,2H),3.52(s,2H),1.30(t,J＝7.1Hz,3H).ESI-MS(m/z):283.3([M+H]+)。
Example 1-b: preparation of (3R) -1-ethyl-4-methyl 2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-methylsuccinate
Figure BDA0001205488580000161
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry Tetrahydrofuran (THF), and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 ℃ and a Tetrahydrofuran (THF) solution of ethyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxobutyrate (25.00g of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate was slowly added dropwise under the protection of nitrogen and dissolved in 100mL of Tetrahydrofuran (THF). After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. The reaction liquid is cooled to 0 ℃, Tetrahydrofuran (THF) solution of (R) -methyl-2- (p-toluenesulfonate) isopropanoate (31.37g of (R) -methyl-2- (p-toluenesulfonate) isopropanoate is slowly dripped and dissolved in 100mL of Tetrahydrofuran (THF), the reaction liquid is heated to 20-30 ℃ after the dripping is finished, and the reaction liquid is stirred and reacted for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials are completely reacted, 150mL of 2NHCl is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted by ethyl acetate for 3 times, the dosage is 100mL each time, organic phases are combined, the organic phases are washed twice by water, the dosage is 200mL each time, the organic phases are combined, the organic phases are concentrated under reduced pressure to obtain 48.60g of oily matter (3R) -1-ethyl-4-methyl 2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-methylsuccinate, and the raw materials are directly fed for the next reaction without purification.
Example 1-c: preparation of (R) -5- ([1,1' -biphenyl ] -4-yl) -2-methyl-4-pentanoic acid
Figure BDA0001205488580000162
To a 500mL reaction flask was added 13.04g of (3R) -1-ethyl-4-methyl 2- (2- ([1,1' -biphenyl)]-4-yl) acetyl) -3-methylsuccinate and 130mL Tetrahydrofuran (THF), cooling the reaction solution to 0 ℃, and slowly adding lithium hydroxide monohydrate (LiOH2O) (3.71g lithium hydroxide monohydrate dissolved in 130mL water). After the dropwise addition, heating the reaction solution to 60-70 ℃, and continuously stirring for reaction for 16 hours. HPLC (high performance liquid chromatography) detection shows that the raw materials completely react, the reaction liquid is cooled to 20-30 ℃, 100mL of 1N HCl aqueous solution is slowly dripped to adjust the pH to 2-3, the reaction liquid is extracted by ethyl acetate for 3 times, the dosage is 100mL each time, organic phases are combined, the organic phases are washed by water twice, the dosage is 200mL each time, the organic phases are combined, and the organic phases are subjected to pressure concentration to obtain oily matter (R) -5- ([1,1' -biphenyl)]8.50g of (E) -4-methyl-2-pentanoic acid, yield 85.1%.1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.61(d,J＝8.1Hz,2H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):283.3([M+H]+)。
Examples 1-d: preparation of (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoic acid
Figure BDA0001205488580000171
Dissolving 100g of isopropylamine in 100ml of water, adjusting the pH value to 7.5-8.0 by using a hydrochloric acid aqueous solution, adding 250ml of dimethyl sulfoxide (DMSO), diluting to 1000ml by using a 0.1M Tris (hydroxymethyl) aminomethane-hydrochloric acid (Tris-HCl) buffer solution, heating to 40 ℃, adding 10g of omega-transaminase freeze-dried powder and 8.0g of pyridoxal phosphate (PLP), and then dropwise adding 100g of (R) -5- ([1,1' -biphenyl)]And (3) 250ml of a dimethyl sulfoxide (DMSO) solution of (E) -4-methyl-4-pentanoic acid, wherein the pH value of the solution is controlled to be 7.5-8.0 by using a 20% isopropylamine aqueous solution in the reaction process, the temperature is kept at 40-45 ℃, the reaction is carried out for more than 24 hours, and the completion of the reaction is monitored by TLC. Filtering to remove solid, extracting mother liquor with ethyl acetate for 3 times, combining, concentrating under reduced pressure, and evaporating to dryness to obtain yellowish solid 90.2g with yield of about 90.2% and ee value of 99%.1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.66(dd,J＝14.2,7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):284.3([M+H]+)。
Examples 1-e: preparation of ethyl (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate
Figure BDA0001205488580000172
70.00g of (2R,4S) -5- ([1,1' -biphenyl) was sequentially added to a 500mL reaction flask]Heating-4-yl) -4-amino-2-methyl pentanoic acid and 350mL of absolute ethyl alcohol to 40 ℃, and stirring to dissolve to obtain a clear solution. Slowly dropping into the reaction solution32.57g of thionyl chloride is added, and after the addition, the temperature is raised to 70 ℃ for reaction. HPLC detection shows that the raw materials react completely, the reaction system is slowly cooled to room temperature, the solvent is removed through reduced pressure distillation to obtain a white solid, 630mL ethyl acetate is added into the obtained solid, the temperature is increased to 60 ℃, stirring is carried out for 2h, the temperature is reduced to 25 ℃, stirring is carried out for 2h, filtering is carried out, and a filter cake is dried in vacuum at 50 ℃ to obtain 70.77g of the white solid with the yield of 92%.1H NMR(600MHz,CDCl3)δ8.62(s,2H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.36-7.29(m,3H),4.07(q,J＝7.1Hz,2H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.20-1.15(m,6H).ESI-MS(m/z):312.4([M+H]+)。
Example 1-f: preparation of Sakubitqu
According to CN104557600A description [0038 ]]Paragraph [0039 ]]According to the method described in example 8, sabotabifonazole was obtained with a yield of 91.8%.1H NMR(400MHz,DMSO)δ7.96(d,J＝8.2Hz,1H),7.62(d,J＝7.4Hz,2H),7.55(d,J＝8.1Hz,2H),7.43(t,J＝7.6Hz,2H),7.33(t,J＝7.3Hz,1H),7.24(d,J＝8.1Hz,2H),4.02–3.86(m,3H),2.74(dd,J＝13.4,6.3Hz,1H),2.64(dd,J＝13.4,6.8Hz,1H),2.50–2.44(m,1H),2.26(dd,J＝22.4,7.3Hz,4H),1.81–1.68(m,1H),1.47–1.36(m,1H),1.10(t,J＝7.1Hz,3H),1.04(d,J＝7.0Hz,3H).ESI-MS(m/z):412.2([M+H]+)。
Example 2
Example 2-a: preparation of tert-butyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutanoate
Figure BDA0001205488580000181
To a 500mL reaction flask were added 10.61g of 4-biphenylacetic acid, 8.65g of Meldrum's acid, 0.61g of 4-Dimethylaminopyridine (DMAP) and 80mL of Dimethylacetamide (DMAC) in this order at room temperature, and the mixture was stirred until it became clear. 13.57g of N, N-Diisopropylethylamine (DIPEA) is slowly dripped into the reaction solution, 6.63g of pivaloyl chloride is slowly dripped after the dripping is finished, and the temperature is raised to 50 ℃ for reaction for 20 hours after the dripping is finished. 18.50g of t-butanol (t-BuOH) was added to the reaction mixture, and the mixture was heated to 100 ℃ to react for 7 hours. HPLC detects the complete reaction of the raw materials, and the reaction liquid is cooled toAdding 200mL of water at 20-30 ℃, extracting the reaction liquid for 3 times by using ethyl acetate, mixing organic phases, washing the organic phases twice by using a saturated NaCl aqueous solution, mixing the organic phases, performing vacuum concentration on the organic phases to obtain tert-butyl 4- ([1,1 '-biphenyl ] with the use of 200mL of saturated NaCl aqueous solution, mixing the organic phases, and performing vacuum concentration on the organic phases to obtain the tert-butyl 4- ([1,1' -biphenyl)]13.34g of (E) -4-yl) -3-oxopentanoate, yield 86%.1H NMR(600MHz,CDCl3)δ7.57(t,J＝6.8Hz,4H),7.43(t,J＝7.4Hz,2H),7.38–7.32(m,1H),7.31–7.25(m,2H),3.87(s,2H),3.41(s,2H),1.47(s,9H).ESI-MS(m/z):311.4([M+H]+)。
Example 2-b: preparation of (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-methylsuccinate
Figure BDA0001205488580000182
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry Tetrahydrofuran (THF), and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 deg.C, and a tetrahydrofuran solution of tert-butyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxopentanoate (25.00g of tert-butyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxopentanoate dissolved in 100mL of tetrahydrofuran) was slowly added dropwise under the protection of nitrogen. After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. Cooling the reaction liquid to 0 ℃, slowly dropwise adding a tetrahydrofuran solution of (R) -methyl-2- (trifluoromethanesulfonic acid group) isopropyl ester (31.37g of (R) -methyl-2- (trifluoromethanesulfonic acid group) isopropyl ester is dissolved in 100mL of tetrahydrofuran), heating the reaction liquid to 20-30 ℃ after the dropwise adding is finished, and stirring for reacting for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials completely react, 150mL of 2N hydrochloric acid is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage is 100mL each time, organic phases are combined, the organic phases are washed twice by water, the dosage is 200mL each time, the organic phases are combined, the organic phases are subjected to pressure concentration to obtain 48.60g of oily matter (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-methylsuccinate, and the oily matter is directly fed for the next reaction without purification.
Example 2-c: preparation of (R) -5- ([1,1' -biphenyl ] -4-yl) -2-methyl-4-pentanoic acid methyl ester
Figure BDA0001205488580000191
To a 100mL reaction flask was added 6.00g of (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl)]-4-yl) acetyl) -3-methylsuccinate, 30mL of Dichloromethane (DCM) and 11.01g of trifluoroacetic acid (CF)3COOH), heating to 42 ℃ under stirring for reaction for 22h, detecting the complete reaction of raw materials by HPLC, adding 150mL of 6.5% sodium bicarbonate solution, slowly dropwise adding 150mL of 2NHCl into the reaction solution to adjust the pH to 2-3, extracting the reaction solution with ethyl acetate for 3 times, wherein the dosage is 100mL each time, combining organic phases, washing the organic phase with water twice, wherein the dosage is 200mL each time, combining the organic phases, and concentrating the organic phase under reduced pressure to obtain oily matter (R) -5- ([1,1' -biphenyl)]4.10g of methyl (4-yl) -2-methyl-4-pentanoate in 91.5% yield.1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.46(t,J＝7.6Hz,2H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),3.78(s,2H),3.69(s,3H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.18(d,J＝6.8Hz,3H).ESI-MS(m/z):297.3([M+H]+)。
Example 2-d: preparation of methyl (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate
Figure BDA0001205488580000192
Dissolving 10g of isopropylamine in 10ml of water, adjusting the pH value to 7.5-8.0 by using a hydrochloric acid aqueous solution, adding 25ml of dimethyl sulfoxide (DMSO), diluting to 100ml by using a 0.1M Tris (hydroxymethyl) aminomethane-hydrochloric acid (Tris-HCl) buffer solution, heating to 40 ℃, adding 1.0g of omega-transaminase freeze-dried powder and 0.8g of pyridoxal phosphate (PLP), and then dropwise adding 10g of (R) -5- ([1,1' -biphenyl)]A 25ml dimethyl sulfoxide (DMSO) solution of methyl (4-yl) -2-methyl-4-pentanoate, wherein the pH value is controlled to be 7.5-8.0 by using a 20% isopropyl amine water solution in the reaction process, the temperature is kept at 40-45 ℃, the reaction is carried out for more than 24 hours, and the TLC is used for monitoring the completion of the reaction. The solid was removed by filtration, the mother liquor was extracted 3 times with ethyl acetate, the combined organic phases were concentrated under reduced pressure and evaporated to dryness to give 8.95g of a pale yellow solid with a yield of about 89.6% and an ee value of 98.5%.1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.65(dd,J＝14.2,7.7Hz,4H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.68(s,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):311.3([M+H]+)。
Example 2-e: preparation of (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoic acid
Figure BDA0001205488580000193
10g of (2R,4S) -5- ([1,1' -biphenyl) was sequentially added to a 250mL reaction flask]-4-yl) -4-amino-2-methyl pentanoic acid methyl ester, 50mL tetrahydrofuran, 50mL methanol and 2.41g lithium hydroxide, stirring and reacting for 12h at 20-40 ℃, monitoring the reaction by TLC, removing the solvent by reduced pressure distillation, adding 100mL water and 100mL ethyl acetate into the residue, stirring for 10 min, separating out the organic phase, concentrating and evaporating to dryness under reduced pressure to obtain 8.19g of light yellow solid with the yield of 86%.1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.66(dd,J＝14.2,7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):284.3([M+H]+)。
Example 2-f: preparation of ethyl (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate
The same as in example 1-e.
Example 2-g: preparation of Sakubitqu
The same as in example 1-f.
Example 3
Example 3-a: preparation of tert-butyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutanoate
The same as in example 2-a.
Example 3-b: preparation of (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-ethylsuccinate
Figure BDA0001205488580000201
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry Tetrahydrofuran (THF), and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 deg.C, and a tetrahydrofuran solution of tert-butyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxopentanoate (25.00g of tert-butyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxopentanoate dissolved in 100mL of tetrahydrofuran) was slowly added dropwise under the protection of nitrogen. After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. Cooling the reaction liquid to 0 ℃, slowly dropwise adding a tetrahydrofuran solution of (R) -ethyl-2- (trifluoromethanesulfonic acid group) isopropyl ester (33.37g of (R) -ethyl-2- (trifluoromethanesulfonic acid group) isopropyl ester is dissolved in 100mL of tetrahydrofuran), heating the reaction liquid to 20-30 ℃ after the dropwise adding is finished, and stirring for reacting for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials completely react, 150mL of 2N HCl is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage is 100mL each time, organic phases are combined, the organic phases are washed twice by water, the dosage is 200mL each time, the organic phases are combined, the organic phases are subjected to pressure concentration to obtain 49.60g of oily matter (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-ethylsuccinate, and the oily matter is directly fed for the next reaction without purification.
Example 3-c: preparation of ethyl (R) -5- ([1,1' -biphenyl ] -4-yl) -2-methyl-4-pentanoate
Figure BDA0001205488580000211
To a 100mL reaction flask was added 6.00g of (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl)]-4-yl) acetyl) -3-ethylsuccinate, 30mL Dichloromethane (DCM) and 11.01g trifluoroacetic acid (CF)3COOH), heating to 42 ℃ under stirring, reacting for 22h, detecting by HPLC that the raw materials react completely, adding 150mL of 6.5% sodium bicarbonate solution, slowly dropwise adding 150mL of 2N HCl into the reaction solution to adjust the pH to 2-3, extracting the reaction solution with ethyl acetate for 3 times with the dosage of 100mL each time, combining organic phases, washing the organic phases with water twice with the dosage of 200mL each time,combining organic phases, and concentrating the organic phase under reduced pressure to obtain oily matter (R) -5- ([1,1' -biphenyl)]4.10g of ethyl (4-yl) -2-methyl-4-pentanoate in 92% yield.1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),4.06(q,J＝7.1Hz,2H),3.78(s,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.20-1.15(m,6H)..ESI-MS(m/z):311.4([M+H]+)。
Example 3-d: preparation of ethyl (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate
Figure BDA0001205488580000212
Dissolving 10g of isopropylamine in 10ml of water, adjusting the pH value to 7.5-8.0 by using a hydrochloric acid aqueous solution, adding 25ml of dimethyl sulfoxide (DMSO), diluting to 100ml by using a 0.1M Tris (hydroxymethyl) aminomethane-hydrochloric acid (Tris-HCl) buffer solution, heating to 40 ℃, adding 1.0g of omega-transaminase freeze-dried powder and 0.8g of pyridoxal phosphate (PLP), and then dropwise adding 10g of (R) -5- ([1,1' -biphenyl)]And (3) 25ml of a dimethyl sulfoxide (DMSO) solution of ethyl (4-yl) -2-methyl-4-pentanoate, wherein the pH value is controlled to be 7.5-8.0 by using a 20% isopropylamine aqueous solution in the reaction process, the temperature is kept at 40-45 ℃, the reaction is carried out for more than 24 hours, and the completion of the reaction is monitored by TLC. Filtering to remove solid, extracting mother liquor with ethyl acetate for 3 times, combining, concentrating under reduced pressure, and evaporating to dryness to obtain light yellow solid 8.80g, with yield of about 88.1% and ee value of 99.0%.1H NMR(600MHz,CDCl3)δ8.62(s,2H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.36-7.29(m,3H),4.07(q,J＝7.1Hz,2H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.20-1.15(m,6H).ESI-MS(m/z):312.4([M+H]+)。
Example 3-e: preparation of Sakubitqu
The same as in example 1-f.
Example 4
Example 4-a: preparation of tert-butyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutanoate
The same as in example 2-a.
Example 4-b: preparation of (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-isopropylsuccinate
Figure BDA0001205488580000221
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry Tetrahydrofuran (THF), and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 deg.C, and a tetrahydrofuran solution of tert-butyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxopentanoate (25.00g of tert-butyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxopentanoate dissolved in 100mL of tetrahydrofuran) was slowly added dropwise under the protection of nitrogen. After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. Cooling the reaction liquid to 0 ℃, slowly dropwise adding a tetrahydrofuran solution of (R) -isopropyl-2- (trifluoromethanesulfonic acid group) isopropyl ester (33.37g of (R) -isopropyl-2- (trifluoromethanesulfonic acid group) isopropyl ester is dissolved in 100mL of tetrahydrofuran), heating the reaction liquid to 20-30 ℃ after the dropwise adding is finished, and stirring for reacting for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials completely react, 150mL of 2N HCl is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage is 100mL each time, organic phases are combined, the organic phases are washed twice by water, the dosage is 200mL each time, the organic phases are combined, the organic phases are concentrated under reduced pressure to obtain 50.60g of oily (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1 '-biphenyl ] -4-yl) acetyl) -3-isopropyl succinate, and the oily (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl ] -4.
Example 4-c: preparation of (R) -benzyl-5- ([1,1' -biphenyl ] -4-yl) -2-methyl-4-pentanone isopropyl ester
Figure BDA0001205488580000222
To a 100mL reaction flask was added 6.00g of (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl)]-4-yl) acetyl) -3-isopropylsuccinate, 30mL Dichloromethane (DCM) and 11.01g trifluoroacetic acid (CF)3COOH) and heating to 42 ℃ under stirring for 22h, detecting the reaction of the raw materials by HPLC, adding 150mL of 6.5% sodium bicarbonate solution, slowly adding 150mL of 2N HCl dropwise into the reaction solution to adjust the pH to 2E3, extracting the reaction liquid for 3 times by using ethyl acetate, wherein the dosage is 100mL each time, combining organic phases, washing the organic phases twice by using water, the dosage is 200mL each time, combining the organic phases, and concentrating the organic phases under reduced pressure to obtain oily matter (R) -5- ([1,1' -biphenyl)]3.80g of isopropyl (E) -4-methyl-4-pentanone, yield 84.8%.1H NMR(600MHz,CDCl3)δ7.60(dt,J＝15.9,6.1Hz,4H),7.47(t,J＝7.7Hz,2H),7.37(dt,J＝9.7,7.9Hz,1H),7.33–7.28(m,2H),4.93(m,1H),3.78(s,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.30(d,J＝7.1Hz,6H),1.18(d,J＝6.8Hz,3H).ESI-MS(m/z):325.4([M+H]+)。
Example 4-d: preparation of (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoic acid isopropyl ester
Figure BDA0001205488580000223
Dissolving 10g of isopropylamine in 10ml of water, adjusting the pH value to 7.5-8.0 by using a hydrochloric acid aqueous solution, adding 25ml of dimethyl sulfoxide (DMSO), diluting to 100ml by using a 0.1M Tris (hydroxymethyl) aminomethane-hydrochloric acid (Tris-HCl) buffer solution, heating to 40 ℃, adding 1.0g of omega-transaminase freeze-dried powder and 0.8g of pyridoxal phosphate (PLP), and then dropwise adding 10g of (R) -5- ([1,1' -biphenyl)]And (3) preparing a 25ml dimethyl sulfoxide (DMSO) solution of isopropyl (4-yl) -2-methyl-4-pentanoate, controlling the pH value to be 7.5-8.0 by using a 20% isopropylamine aqueous solution in the reaction process, keeping the temperature to be 40-45 ℃, reacting for more than 24 hours, and monitoring the completion of the reaction by TLC. The solid was removed by filtration, the mother liquor was extracted 3 times with ethyl acetate, the combined organic phases were concentrated under reduced pressure and evaporated to dryness to give 8.20g of a pale yellow solid with a yield of about 82.1% and an ee value of 96.5%.1H NMR(600MHz,CDCl3)δ8.62(s,2H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.36-7.29(m,3H),4.93(m,1H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.31(d,J＝7.1Hz,6H),1.17(d,J＝6.8Hz,3H).ESI-MS(m/z):326.4([M+H]+)。
Example 4-e: preparation of (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoic acid
Figure BDA0001205488580000231
10g of (2R,4S) -5- ([1,1' -biphenyl) was sequentially added to a 250mL reaction flask]-4-yl) -4-amino-2-methyl isopropyl valerate, 50mL tetrahydrofuran, 50mL methanol and 2.65g sodium hydroxide, stirring and reacting for 12h at 20-40 ℃, monitoring the reaction by TLC after completion, removing the solvent by reduced pressure distillation, adding 100mL water and 100mL ethyl acetate into the residue, stirring for 10 min, separating out the organic phase, concentrating under reduced pressure and evaporating to dryness to obtain 7.40g of light yellow solid with the yield of 85%.1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.66(dd,J＝14.2,7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):284.3([M+H]+)。
Example 4-f: preparation of ethyl (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate
The same as in example 1-e.
Example 4-g: preparation of Sakubitqu
The same as in example 1-f.
Example 5
Example 5-a: preparation of tert-butyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutanoate
Figure BDA0001205488580000232
20.00g of 4-biphenylacetic acid, 14.96g of Meldrum's acid, 0.61g of 4-Dimethylaminopyridine (DMAP), 21.40g N, N' -Dicyclohexylcarbodiimide (DCC) and 200mL of methylene chloride were sequentially added to a 1L reaction flask at room temperature, and the temperature was lowered to 0 ℃ to react for 12 hours. Filtration was carried out to remove the precipitated solid by filtration, and the filtrate was concentrated to dryness to give a pale yellow oil. 95mL of tert-butanol was added to the above oil, and the mixture was heated to 82 ℃ under nitrogen protection to react. TLC detection of the reaction completion of the raw materials, vacuum distillation of the reaction solution to remove tert-butanol, addition of 100mL dichloromethane, washing with water and saturated aqueous sodium chloride solution, and collectionEvaporating the organic phase under reduced pressure to remove the solvent to obtain tert-butyl 4- ([1,1' -biphenyl)]24.89g of (E) -4-yl) -3-oxobutanoic acid ester, yield 85%.1H NMR(600MHz,CDCl3)δ7.57(t,J＝6.8Hz,4H),7.43(t,J＝7.4Hz,2H),7.38–7.32(m,1H),7.31–7.25(m,2H),3.87(s,2H),3.41(s,2H),1.47(s,9H).ESI-MS(m/z):311.4([M+H]+)。
Example 5-b: preparation of (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-benzylsuccinate
Figure BDA0001205488580000241
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry Tetrahydrofuran (THF), and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 deg.C, and a tetrahydrofuran solution of tert-butyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxopentanoate (25.00g of tert-butyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxopentanoate dissolved in 100mL of tetrahydrofuran) was slowly added dropwise under the protection of nitrogen. After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. Cooling the reaction liquid to 0 ℃, slowly dropwise adding a tetrahydrofuran solution of (R) -benzyl-2- (trifluoromethanesulfonic acid group) isopropyl ester (33.37g of (R) -benzyl-2- (trifluoromethanesulfonic acid group) isopropyl ester is dissolved in 100mL of tetrahydrofuran), heating the reaction liquid to 20-30 ℃ after the dropwise adding is finished, and stirring for reacting for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials completely react, 150mL of 2N HCl is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage is 100mL each time, organic phases are combined, the organic phases are washed twice by water, the dosage is 200mL each time, the organic phases are combined, the organic phases are concentrated under reduced pressure to obtain 50.60g of oily (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1 '-biphenyl ] -4-yl) acetyl) -3-benzylsuccinate, and the oily (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl ] -.
Example 5-c: preparation of benzyl (R) -benzyl-5- ([1,1' -biphenyl ] -4-yl) -2-methyl-4-pentanoate
Figure BDA0001205488580000242
To a 100mL reaction flask was added 6.00g of (3R) -1-tert-butyl-4-methyl-2- (2- ([1,1' -biphenyl)]-4-yl) acetyl) -3-benzylsuccinate, 30mL Dichloromethane (DCM) and 11.01g trifluoroacetic acid (CF)3COOH), heating to 42 ℃ under stirring for reaction for 22h, detecting by HPLC that the raw materials react completely, adding 150mL of 6.5% sodium bicarbonate solution, slowly dropwise adding 150mL of 2N HCl into the reaction solution to adjust the pH to 2-3, extracting the reaction solution with ethyl acetate for 3 times, wherein the dosage is 100mL each time, combining organic phases, washing the organic phases with water twice, wherein the dosage is 200mL each time, combining the organic phases, and concentrating the organic phases under reduced pressure to obtain oily matter (R) -5- ([1,1' -biphenyl)]Benzyl (4-yl) -2-methyl-4-pentanoate 4.10g, 91.5% yield.1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.46(t,J＝7.6Hz,2H),7.40-7.33(m,5H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),5.22(s,2H),3.78(s,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.18(d,J＝6.8Hz,3H).ESI-MS(m/z):373.5([M+H]+)。
Example 5-d: preparation of benzyl (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate
Figure BDA0001205488580000251
Dissolving 10g of isopropylamine in 10ml of water, adjusting the pH value to 7.5-8.0 by using a hydrochloric acid aqueous solution, adding 25ml of dimethyl sulfoxide (DMSO), diluting to 100ml by using a 0.1M Tris (hydroxymethyl) aminomethane-hydrochloric acid (Tris-HCl) buffer solution, heating to 40 ℃, adding 1.0g of omega-transaminase freeze-dried powder and 0.8g of pyridoxal phosphate (PLP), and then dropwise adding 10g of (R) -5- ([1,1' -biphenyl)]A 25ml dimethyl sulfoxide (DMSO) solution of benzyl (4-yl) -2-methyl-4-pentanoate, wherein the pH value is controlled to be 7.5-8.0 by using a 20% isopropyl amine aqueous solution during the reaction, the temperature is kept at 40-45 ℃ for reaction for more than 24 hours, and the TLC is used for monitoring the completion of the reaction. The solid was removed by filtration, the mother liquor was extracted 3 times with ethyl acetate, the combined organic phases were concentrated under reduced pressure and evaporated to dryness to give 7.90g of a pale yellow solid with a yield of about 79.1% and an ee value of 88.0%.1H NMR(600MHz,CDCl3)δ8.62(s,2H),7.54(dd,J＝14.1,7.7Hz,4H),7.41(t,J＝7.6Hz,2H),7.40-7.33(m,5H),7.36-7.29(m,3H),5.22(s,2H),3.67(s,1H),3.40-3.34(m,1H),2.97(dd,J＝24.3,10.9Hz,2H),2.07-2.00(m,1H),1.90-1.83(m,1H),1.15(d,J＝6.8Hz,3H).ESI-MS(m/z):374.4([M+H]+)。
Example 5-e: preparation of (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoic acid
Figure BDA0001205488580000252
10g of (2R,4S) -5- ([1,1' -biphenyl) was sequentially added to a 250mL reaction flask]Benzyl (4-yl) -4-amino-2-methylpentanoate, 50mL tetrahydrofuran, 50mL methanol and 2.65g sodium hydroxide were stirred at 20-40 ℃ for 12h, TLC monitored completion of the reaction, the solvent was removed by distillation under reduced pressure, 100mL water and 100mL ethyl acetate were added to the residue, stirred for 10 min, the organic phase was separated, concentrated under reduced pressure and evaporated to dryness to give 6.22g of a pale yellow solid in 82% yield.1H NMR(600MHz,DMSO-d6)δ8.22(s,2H),7.66(dd,J＝14.2,7.7Hz,4H),7.47(t,J＝7.7Hz,2H),7.36(t,J＝8.0Hz,3H),3.43(d,J＝5.4Hz,1H),3.05(dd,J＝13.9,5.7Hz,1H),2.86(dd,J＝13.9,7.7Hz,1H),2.66(m,J＝13.9,7.0Hz,1H),1.86(m,J＝14.2,8.7,5.5Hz,1H),1.59(m,J＝13.9,7.7,5.9Hz,1H),1.07(d,J＝7.0Hz,3H).ESI-MS(m/z):284.3([M+H]+)。
Example 5-f: preparation of ethyl (2R,4S) -5- ([1,1' -biphenyl ] -4-yl) -4-amino-2-methylpentanoate
The same as in example 1-e.
Example 5-g: preparation of Sakubitqu
The same as in example 1-f.
Example 6
Example 6-a: preparation of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate
The same as in example 1-a.
Example 6-b: preparation of ethyl (3R) - -2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-methyl-4-methylamino-4-oxobutanoate
Figure BDA0001205488580000261
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry Tetrahydrofuran (THF), and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 ℃ and a Tetrahydrofuran (THF) solution of ethyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxobutyrate (25.00g of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate was slowly added dropwise under the protection of nitrogen and dissolved in 100mL of Tetrahydrofuran (THF). After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. The reaction liquid is cooled to 0 ℃, a Tetrahydrofuran (THF) solution of (R) -methyl-2- (p-toluenesulfonate) formamide (31.37g of (R) -methyl-2- (p-toluenesulfonate) formamide is slowly dripped and dissolved in 100mL of THF, the reaction liquid is heated to 20-30 ℃ after dripping, and stirring reaction is carried out for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials completely react, 150mL of 2N hydrochloric acid is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage is 100mL each time, organic phases are combined, the organic phases are washed twice by water, the dosage is 200mL each time, the organic phases are combined, the organic phases are concentrated under reduced pressure to obtain 48.60g of oily (3R) -2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-methyl-4-methylamino-4-oxobutyric acid ethyl ester, and the raw materials are directly fed for the next reaction without purification.
Example 6-c: preparation of (R) -5- ([1,1' -biphenyl ] -4-yl) -N, 2-dimethyl-4-oxopentanamide
Figure BDA0001205488580000262
15.00g of (3R) -2- (2- ([1,1' -biphenyl) was added to a 500mL reaction flask]-4-yl) acetyl) -3-methyl-4-methylamino-4-oxobutanoic acid ethyl ester and 130mL Tetrahydrofuran (THF), the reaction solution was cooled to 0 ℃, and lithium hydroxide monohydrate (lioh2O) (4.00g of lithium hydroxide monohydrate dissolved in 130mL of water). After the dropwise addition, heating the reaction solution to 60-70 ℃, and continuously stirring for reaction for 16 hours. HPLC (high performance liquid chromatography) detection shows that the raw materials completely react, the temperature of the reaction liquid is reduced to 20-30 ℃, 100mL of 1N HCl aqueous solution is slowly dripped to adjust the pH to 2-3, the reaction liquid is extracted by ethyl acetate for 3 times, the dosage is 100mL each time, organic phases are combined, the organic phase is washed by water twice, the dosage is 200mL each time, and the organic phase is subjected to pressure concentration to obtain oily matter (R) -5- ([1,1' -biphenyl)]-4-yl) -N, 2-dimethyl10.43g of phenyl-4-oxovaleramide, yield 86.5%.1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.61(d,J＝8.1Hz,2H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),3.05(s,3H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):296.3([M+H]+)。
Example 7
Example 7-a: preparation of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate
The same as in example 1-a.
Example 7-b: preparation of (3R) - -2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-methyl-4-tert-butylamino-4-oxo-butyric acid ethyl ester
Figure BDA0001205488580000271
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry Tetrahydrofuran (THF), and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 ℃ and a Tetrahydrofuran (THF) solution of ethyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxobutyrate (25.00g of 4- ([1,1' -biphenyl ] -4-yl) -3-oxo-butyrate was dissolved in 100mL of Tetrahydrofuran (THF) was slowly added dropwise under the protection of nitrogen. After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. The reaction liquid is cooled to 0 ℃, a Tetrahydrofuran (THF) solution of (R) -methyl-2- (p-toluenesulfonate) tert-butyramide (31.37g of (R) -methyl-2- (p-toluenesulfonate) tert-butyramide is slowly dripped into the solution and dissolved in 100mL of THF, after dripping, the reaction liquid is heated to 20-30 ℃, and is stirred for reaction for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials completely react, 150mL of 2N hydrochloric acid is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage of each time is 100mL, organic phases are combined, the organic phases are washed twice by water, the dosage of each time is 200mL, the organic phases are subjected to pressure concentration to obtain 48.60g of oily (3R) -2- (2- ([1,1' -biphenyl ] -4-yl) acetyl) -3-methyl-4-tert-butylamino-4-oxo-ethyl butyrate, and the materials are directly fed for the next reaction without purification.
Example 7-c: preparation of (R) -5- ([1,1' -biphenyl ] -4-yl) -N-tert-butyl-2-methyl-4-oxopentanamide
Figure BDA0001205488580000272
15.00g of (3R) -2- (2- ([1,1' -biphenyl) was added to a 500mL reaction flask]-4-yl) acetyl) -3-methyl-4-tert-butylamino-4-oxo-butyric acid ethyl ester and 130mL Tetrahydrofuran (THF), cooling the reaction solution to 0 ℃, and slowly adding lithium hydroxide monohydrate (LiOH2O) (4.00g of lithium hydroxide monohydrate dissolved in 130mL of water). After the dropwise addition, heating the reaction solution to 60-70 ℃, and continuously stirring for reaction for 16 hours. HPLC (high performance liquid chromatography) detection shows that the raw materials completely react, the reaction liquid is cooled to 20-30 ℃, 100mL of 1N hydrochloric acid aqueous solution is slowly dripped to adjust the pH to 2-3, the reaction liquid is extracted by ethyl acetate for 3 times, the dosage is 100mL each time, organic phases are combined, the organic phases are washed by water for two times, the dosage is 200mL each time, the organic phases are combined, and the organic phases are subjected to pressure concentration to obtain oily matter (R) -5- ([1,1' -biphenyl)]-4-yl) -N-tert-butyl-2-methyl-4-oxovaleramide 10.05g, 81.3% yield.1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.61(d,J＝8.1Hz,2H),7.46(t,J＝7.7Hz,2H),7.36(t,J＝7.4Hz,1H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.39(s,9H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):338.4([M+H]+)。
Example 8
Example 8-a: preparation of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate
The same as in example 1-a.
Example 8-b: preparation of (2R) -4- (4- ([1,1' -biphenyl ] -4-yl)) -3-oxo-2- (1- (triphenylmethoxy) propan-2-yl) -butyric acid ethyl ester
Figure BDA0001205488580000281
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry toluene, and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 ℃ and a toluene solution of ethyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxobutyrate (25.00g of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate was dissolved in 100mL of toluene) was slowly added dropwise under the protection of nitrogen. After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. Cooling the reaction liquid to 0 ℃, slowly dropwise adding a toluene solution of (R) -methyl-2- (p-toluenesulfonate) triphenyl methyl ether (31.37g of (R) -methyl-2- (p-toluenesulfonate) triphenyl methyl ether dissolved in 100mL of toluene), heating the reaction liquid to 60-70 ℃ after the dropwise adding is finished, and stirring for reacting for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials are completely reacted, 150mL of 2NHCl is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage is 100mL each time, organic phases are combined, the organic phases are washed twice by water and 200mL each time, the organic phases are combined, the organic phases are subjected to pressure concentration by the organic phases to obtain 46.60g of oily matter (2R) -4- (4- ([1,1' -biphenyl ] -4-yl)) -3-oxo-2- (1- (triphenylmethoxy) propane-2-yl) -ethyl butyrate, and the raw materials are directly fed for the next reaction without purification.
Example 8-c: preparation of (R) -5- ([1,1' -biphenyl ] -4-yl) -2-methyl-1- (triphenylmethoxy) -4-pentanone
Figure BDA0001205488580000282
15.00g of (2R) -4- (4- ([1,1' -biphenyl) was added to a 500mL reaction flask]-4-yl)) -3-oxo-2- (1- (trityloxy) propan-2-yl) -butyric acid ethyl ester and 130mL Tetrahydrofuran (THF), cooling the reaction to 0 ℃, and slowly adding lithium hydroxide monohydrate (lioh2O) (4.00g of lithium hydroxide monohydrate dissolved in 130mL of water). After the dropwise addition, heating the reaction solution to 60-70 ℃, and continuously stirring for reaction for 16 hours. HPLC (high performance liquid chromatography) detection shows that the raw materials completely react, the reaction liquid is cooled to 20-30 ℃, 100mL of 1N HCl aqueous solution is slowly dripped to adjust the pH to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage is 100mL each time, organic phases are combined, the organic phase is washed twice by water, the dosage is 200mL each time, and the organic phase is subjected to pressure concentration to obtain oily matter (R) -5- ([1,1' -biphenyl)]11.24g of (E) -4-methyl-1- (trityloxy) -4-pentanone (yield 85.6%).1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.46(t,J＝7.6Hz,2H),7.40-7.33(m,5H),7.38(m,15H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),3.71(s,2H),3.21(d,J＝6.8Hz,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.18(d,J＝6.8Hz,3H).ESI-MS(m/z):511.6([M+H]+)。
Example 9
Example 9-a: preparation of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate
The same as in example 1-a.
Example 9-b: preparation of (2R) -4- (4- ([1,1' -biphenyl ] -4-yl)) -3-oxo-2- (1- (triethylsiloxy) -2-propanol) -butyric acid ethyl ester
Figure BDA0001205488580000291
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry toluene, and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 ℃ and a toluene solution of ethyl 4- ([1,1 '-biphenyl ] -4-yl) -3-oxobutyrate (25.00g of ethyl 4- ([1,1' -biphenyl ] -4-yl) -3-oxobutyrate was dissolved in 100mL of toluene) was slowly added dropwise under the protection of nitrogen. After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. Cooling the reaction liquid to 0 ℃, slowly dropwise adding a toluene solution of (R) -methyl-2- (p-toluenesulfonyl) triethylsilyl ether (31.37g of (R) -methyl-2- (p-toluenesulfonyl) triethylsilyl ether is dissolved in 100mL of toluene), heating the reaction liquid to 60-70 ℃ after dropwise adding, and stirring for reacting for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials completely react, 150mL of 2N hydrochloric acid is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage of each time is 100mL, organic phases are combined, the organic phases are washed twice by water, the dosage of each time is 200mL, the organic phases are subjected to pressure concentration to obtain 44.50g of oily matter (2R) -4- (4- ([1,1' -biphenyl ] -4-yl)) -3-oxo-2- (1- (triethylsiloxy) -2-propanol) -ethyl butyrate, and the raw materials are directly fed without purification for the next reaction.
Example 9-c: preparation of (R) -5- ([1,1' -biphenyl ] -4-yl) -2-methyl-1- (triethylsiloxy) -4-pentanone
Figure BDA0001205488580000292
15.00g of (2R) -4- (4- ([1,1' -biphenyl) was added to a 500mL reaction flask]-4-yl)) -3-oxo-2- (1- (triethylsiloxy) -2-propanol) -butyric acid ethyl ester and 130mL Tetrahydrofuran (THF), cooling the reaction solution to 0 ℃, and slowly adding lithium hydroxide monohydrate (LiOH2O) (4.00g of lithium hydroxide monohydrate dissolved in 130mL of water). After the dropwise addition, heating the reaction solution to 60-70 ℃, and continuously stirring for reaction for 16 hours. HPLC (high performance liquid chromatography) detection shows that the raw materials completely react, the temperature of the reaction liquid is reduced to 20-30 ℃, 100mL of 1N HCl aqueous solution is slowly dripped to adjust the pH to 2-3, the reaction liquid is extracted by ethyl acetate for 3 times, the dosage is 100mL each time, organic phases are combined, the organic phase is washed by water twice, the dosage is 200mL each time, and the organic phase is subjected to pressure concentration to obtain oily matter (R) -5- ([1,1' -biphenyl)]10.97g of (E) -4-methyl-1- (triethylsiloxy) -4-pentanone (yield: 86.9%).1H NMR(400MHz,CDCl3)δ7.60(t,J＝7.7Hz,4H),7.46(t,J＝7.6Hz,2H),7.40-7.33(m,5H),7.37(t,J＝7.3Hz,1H),7.30(d,J＝8.1Hz,2H),3.71(s,2H),3.63(m,2H),3.04–2.94(m,2H),2.60–2.51(m,1H),1.36(m,6H),1.18(m,12H).ESI-MS(m/z):383.6([M+H]+)。
Example 10
Example 10-a: preparation of ethyl 4- ([ 4-iodophenyl ] -4-yl) -3-oxobutanoate
Figure BDA0001205488580000301
To a 500mL three-necked reaction flask A, 200mL of ethyl acetate and 28.64g N, N' -carbonyldiimidazole were added at room temperature, and 25.00g of 4-iodophenylacetic acid was added in portions to the reaction flask A, and the gas generation rate was controlled. And after the feeding is finished, heating the reaction solution to 45 ℃ for reaction for 3h, cooling to 20-30 ℃, and vacuumizing for 1h under reduced pressure for later use. To a 1L reaction flask B at room temperature were added 280mL of ethyl acetate and 28.06g of EtO2CCH2COOK and 15.70g magnesium chloride (MgCl)2) And controlling the temperature to be 20-30 ℃, slowly dropwise adding 19.07g of Triethylamine (TEA), and continuously stirring for 1h after dropwise adding is finished. And adding the materials in the reaction bottle A into the reaction bottle B at room temperature, heating to 45 ℃, and carrying out heat preservation reaction for 16 hours. Cooling the reaction liquid to 20-30 ℃, and slowly cooling180mL of 4N hydrochloric acid solution was added dropwise, the solution was separated, the organic phase was washed three times with 250mL of 6.5% sodium bicarbonate solution each time, the organic phase was collected, and the solvent was evaporated at 45 ℃ under reduced pressure to give a yellowish brown oil. Adding 150mL of normal hexane into the obtained oily matter, stirring for 18h at 20-30 ℃, filtering, washing a filter cake with the normal hexane, and drying for 5h under vacuum at 40-50 ℃ to obtain 4- ([ 4-iodophenyl)]27.4g of ethyl (4-yl) -3-oxobutanoate, yield 86.5%. 1H NMR (600MHz, CDCl)3)δ,7.47(t,J＝7.7Hz,2H),7.33–7.28(m,2H),4.25–4.18(m,2H),3.90(s,2H),3.52(s,2H),1.30(t,J＝7.1Hz,3H).ESI-MS(m/z):333.1([M+H]+)。
Example 10-b: preparation of (3R) -1-ethyl-4-methyl 2- (2- ([ 4-iodophenyl ] -4-yl) acetyl) -3-methylsuccinate
Figure BDA0001205488580000302
A500 mL reaction flask was charged with 5.31g of sodium hydride (NaH) and 100mL of dry Tetrahydrofuran (THF), and the nitrogen gas was replaced 3 times. The reaction solution was cooled to 0 ℃ and a Tetrahydrofuran (THF) solution of ethyl 4- ([ 4-iodophenyl ] -4-yl) -3-oxobutyrate (25.00g of ethyl 4- ([ 4-iodophenyl ] -4-yl) -3-oxobutyrate was slowly added dropwise under the protection of nitrogen and dissolved in 100mL of Tetrahydrofuran (THF). After the dropwise addition, heating the reaction solution to 20-30 ℃, and continuing stirring for 30 minutes. The reaction liquid is cooled to 0 ℃, Tetrahydrofuran (THF) solution of (R) -methyl-2- (p-toluenesulfonate) isopropanoate (31.37g of (R) -methyl-2- (p-toluenesulfonate) isopropanoate is slowly dripped and dissolved in 100mL of Tetrahydrofuran (THF), the reaction liquid is heated to 20-30 ℃ after the dripping is finished, and the reaction liquid is stirred and reacted for 1.5 h. HPLC (high performance liquid chromatography) detects that the raw materials completely react, 150mL of 2N hydrochloric acid is slowly dripped into the reaction liquid to adjust the pH value to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage of each time is 100mL, organic phases are combined, the organic phases are washed twice by water, the dosage of each time is 200mL, oily matter (3R) -1-ethyl-4-methyl 2- (2- ([ 4-iodophenyl ] -4-yl) acetyl) -3-methylsuccinate 48.60g is obtained by reduced pressure concentration, and the next reaction is directly carried out by feeding without purification.
Example 10-c: preparation of (R) -5- ([ 4-iodophenyl ] -4-yl) -2-methyl-4-pentanoic acid
Figure BDA0001205488580000311
To a 500mL reaction flask was added 13.00g of (3R) -1-ethyl-4-methyl 2- (2- ([ 4-iodophenyl group)]-4-yl) acetyl) -3-methylsuccinate and 130mL Tetrahydrofuran (THF), cooling the reaction solution to 0 ℃, and slowly adding lithium hydroxide monohydrate (LiOH2O) (3.71g lithium hydroxide monohydrate dissolved in 130mL water). After the dropwise addition, heating the reaction solution to 60-70 ℃, and continuously stirring for reaction for 16 hours. HPLC (high performance liquid chromatography) detection shows that the raw materials completely react, the temperature of reaction liquid is reduced to 20-30 ℃, 100mL of 1N hydrochloric acid aqueous solution is slowly dripped to adjust the pH to 2-3, the reaction liquid is extracted for 3 times by ethyl acetate, the dosage is 100mL each time, organic phases are combined, the organic phases are washed twice by water, the dosage is 200mL each time, and oil (R) -5- ([ 4-iodophenyl) is obtained by decompression and concentration]8.46g of (E) -4-methyl-2-pentanoic acid, yield 82.0%.1H NMR(600MHz,DMSO-d6)δ12.16(s,1H),7.66(d,J＝7.3Hz,2H),7.28(d,J＝8.1Hz,2H),3.82(s,2H),2.88(dd,J＝17.7,8.1Hz,1H),2.76–2.69(m,1H),2.61(dd,J＝17.7,5.4Hz,1H),1.05(dd,J＝16.4,7.1Hz,3H).ESI-MS(m/z):333.1([M+H]+)。
In summary, the synthesis method provided by the present invention can effectively prepare the compound represented by formula (04), and further synthesize shakubiqu from the compound represented by formula (04). The method has the advantages of easily available raw materials, simple process, economy, environmental protection and the like.
While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the context, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims (25)

1. A compound shown as a formula (04),
Figure FDA0002884867900000011
wherein R is1Is phenyl;
wherein R is2Is that
Figure FDA0002884867900000012
R3Is hydrogen, - (C)1-C4) Alkyl or benzyl;
R4is tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl or benzyl.
2. The compound of claim 1, wherein R is1Is phenyl.
3. The compound of claim 1, wherein R is3Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl.
4. The compound of claim 1, wherein R is4Is trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl or benzyl.
5. The compound of claim 1, wherein R is2is-COOH, -COOCH3、-COOCH2CH3、-COOCH(CH3)2、-COOC(CH3)3、-COOCH2Ph、-CH2OC(CH3)3、-CH2OCH2Ph、-CH2OC(Ph)3、-CH2OSi(CH3)3、-CH2OSi(CH2CH3)3、-CH2OSi(CH3)2C(CH3)3、-CONH2、-CONHCH3、-CONHCH2CH3、-CONHCH(CH3)2、-CONHC(CH3)3or-CONHCH2Ph。
6. The compound of claim 1, having the structure of one of:
Figure FDA0002884867900000013
Figure FDA0002884867900000021
7. a method for preparing a compound shown as a formula (04),
Figure FDA0002884867900000022
wherein R is1Is phenyl;
wherein R is2Is that
Figure FDA0002884867900000023
R3Is hydrogen, - (C)1-C4) Alkyl or benzyl;
R4is tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl or benzyl;
which is obtained by deprotection reaction of a compound represented by the formula (03),
Figure FDA0002884867900000031
said R1And R2Is as described aboveThe above-mentioned groups;
said R5Is hydrogen, - (C)1-C4) Alkyl or benzyl.
8. The method of claim 7, wherein the first and second light sources are selected from the group consisting of,
wherein R is1Is phenyl;
wherein R is2Is that
Figure FDA0002884867900000032
R3Is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl;
wherein R is5Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl.
9. The method according to claim 8, wherein the compound represented by formula (03) is subjected to deprotection reaction in the presence of an acid or a base to obtain a compound represented by formula (04).
10. The method according to claim 7, 8 or 9, wherein the compound represented by the formula (03) is obtained by subjecting a compound represented by the formula (01) and a compound represented by the formula (02) to a substitution reaction,
Figure FDA0002884867900000033
said R6Is trifluoromethanesulfonic acid group, methanesulfonic acid group or p-toluenesulfonic acid group.
11. The method according to claim 10, wherein the compound represented by formula (03) is obtained by subjecting a compound represented by formula (01) and a compound represented by formula (02) to a substitution reaction in the presence of a strong base.
12. The method according to claim 10, wherein the compound represented by the formula (01) is prepared by performing a condensation reaction on the compound represented by the formula (00),
Figure FDA0002884867900000034
13. the method according to claim 12, wherein the compound represented by the formula (01) is obtained by condensation reaction of a compound represented by the formula (00) as a starting material with N, N' -carbonyldiimidazole and a compound represented by the formula (07) in the presence of magnesium chloride and triethylamine,
Figure FDA0002884867900000035
said R5Is hydrogen, - (C)1-C4) Alkyl or benzyl.
14. The method according to claim 12, wherein the compound represented by the formula (01) is prepared by using a compound represented by the formula (00) as a starting material,
with Meldrum's acid, 4-dimethylaminopyridine and R in the presence of N, N-diisopropylethylamine5OH and pivaloyl chloride are subjected to condensation reaction to obtain the compound R5Is hydrogen, - (C)1-C4) Alkyl or benzyl.
15. A process for producing a compound represented by the formula (04),
Figure FDA0002884867900000041
wherein R is1Is phenyl;
wherein R is2Is that
Figure FDA0002884867900000042
R3Is hydrogen, - (C)1-C4) Alkyl or benzyl;
R4is tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl or benzyl;
the method comprises the following steps:
a) carrying out substitution reaction on the compound shown in the formula (01) and the compound shown in the formula (02) to prepare a compound shown in the formula (03);
Figure FDA0002884867900000043
said R1、R2Is a group as described above, and is,
said R5Is hydrogen, - (C)1-C4) An alkyl group or a benzyl group, or a substituted or unsubstituted alkyl group,
said R6Is trifluoromethanesulfonic acid group, methanesulfonic acid group or p-toluenesulfonic acid group;
b) the compound shown in the formula (03) is subjected to deprotection reaction to prepare the compound shown in the formula (04).
16. A process for producing a compound represented by the formula (04),
Figure FDA0002884867900000044
wherein R is1Is phenyl;
wherein R is2Is that
Figure FDA0002884867900000045
R3Is hydrogen, - (C)1-C4) Alkyl or benzyl;
R4is tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl or benzyl;
the method comprises the following steps:
a) taking a compound shown in a formula (00) as a starting material, and preparing a compound shown in a formula (01) through a condensation reaction;
Figure FDA0002884867900000051
said R1Is a group as described above, and is,
said R5Is hydrogen, - (C)1-C4) Alkyl or benzyl;
b) carrying out substitution reaction on the compound shown in the formula (01) and the compound shown in the formula (02) to prepare a compound shown in the formula (03);
Figure FDA0002884867900000052
said R1、R2And R5Is a group as described above, and is,
said R6Is trifluoromethanesulfonic acid group, methanesulfonic acid group or p-toluenesulfonic acid group;
c) the compound shown in the formula (03) is subjected to deprotection reaction to prepare the compound shown in the formula (04).
17. A process for producing a compound represented by the formula (04),
Figure FDA0002884867900000053
wherein R is1Is a phenyl group, and the phenyl group,
wherein R is2Is that
Figure FDA0002884867900000054
R3Is hydrogen or methylAlkyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl;
R4is tert-butyl, benzyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl or trityl;
the method comprises the following steps:
a) taking a compound shown in a formula (00) as a starting material, and carrying out a condensation reaction under an alkaline condition to prepare a compound shown in a formula (01);
Figure FDA0002884867900000055
said R1Is a group as described above, and is,
said R5Is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl or benzyl;
b) carrying out substitution reaction on the compound shown in the formula (01) and the compound shown in the formula (02) under a strong alkali condition to prepare a compound shown in the formula (03),
Figure FDA0002884867900000061
said R1、R2And R5Is a group as described above, and is,
the R is6Is trifluoromethanesulfonic acid group, methanesulfonic acid group or p-toluenesulfonic acid group;
c) the compound shown in the formula (03) is subjected to deprotection reaction under the condition of acid or alkali to prepare the compound shown in the formula (04).
18. A method of preparing shakubiqu, comprising the steps of:
Figure FDA0002884867900000062
preparing shakubitrex by using the compound shown in the formula (04),
Figure FDA0002884867900000063
wherein the content of the first and second substances,
said R1Is phenyl;
said R2Is that
Figure FDA0002884867900000064
R3Is hydrogen, - (C)1-C4) Alkyl or benzyl;
R4is tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl or benzyl.
19. A method of preparing shakubiqu, comprising the steps of:
Figure FDA0002884867900000065
preparing shakubitrex by using the compound shown in the formula (04),
Figure FDA0002884867900000066
wherein R is1Is benzene, and the benzene is benzene, toluene, xylene, or mixtures thereof,
wherein R is2Is that
Figure FDA0002884867900000071
R3Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl.
20. A method of preparing shakubiqu, comprising the steps of:
Figure FDA0002884867900000072
a) the compound shown in the formula (04) is used as a starting material, and the compound shown in the formula (05) is prepared through an enzyme catalytic reaction,
Figure FDA0002884867900000073
wherein the content of the first and second substances,
said R1Is phenyl;
said R2Is that
Figure FDA0002884867900000074
R3Is hydrogen, - (C)1-C4) An alkyl group or a benzyl group, or a substituted or unsubstituted alkyl group,
R4is tert-butyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, trityl or benzyl;
b) preparation of Compound represented by formula (06) from Compound represented by formula (05)
Figure FDA0002884867900000075
c) The compound shown in the formula (06) and succinic anhydride are subjected to amidation condensation reaction to prepare the shakubiqu.
21. A method of preparing shakubiqu, comprising the steps of:
Figure FDA0002884867900000076
a) the compound shown in the formula (04) is used as a starting material, and the compound shown in the formula (05) is prepared through an enzyme catalytic reaction,
Figure FDA0002884867900000077
wherein R is1Is benzene, and the benzene is benzene, toluene, xylene, or mixtures thereof,
wherein R is2Is that
Figure FDA0002884867900000081
R3Is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl or benzyl;
b) preparing a compound represented by formula (06) from a compound represented by formula (05),
Figure FDA0002884867900000082
c) the compound shown in the formula (06) and succinic anhydride are subjected to amidation condensation reaction to prepare the shakubiqu.
22. The process for producing shakubitril according to claim 20 or 21, wherein the enzyme-catalyzed reaction is carried out in the presence of ω -transaminase and pyridoxal phosphate.
23. The method for preparing shakubitrex according to claim 20 or 21, wherein the compound represented by formula (06) in step b) is prepared by first performing hydrolysis reaction on the compound represented by formula (05) and then performing esterification reaction on the compound with ethanol.
24. A method of preparing shakubiqu, comprising the steps of:
Figure FDA0002884867900000083
a) the compound shown in the formula (04) is used as a starting material, and the compound shown in the formula (05) is prepared through an enzyme catalytic reaction,
Figure FDA0002884867900000084
wherein R is1Is benzene, and the benzene is benzene, toluene, xylene, or mixtures thereof,
wherein R is2Is that
Figure FDA0002884867900000085
R3Is an ethyl group;
b) the compound shown in the formula (06) and succinic anhydride are subjected to amidation condensation reaction to prepare the shakubiqu.
25. Use of a compound according to claims 1-6 for the synthetic preparation of sabotabifentre.
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4604383A (en) * 1983-07-12 1986-08-05 Societe Anonyme Styled: Sanofi Pyrrolidin-2-ones and medicaments containing them
WO2008031567A1 (en) * 2006-09-13 2008-03-20 Novartis Ag Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of nep inhibitors
WO2008083967A2 (en) * 2007-01-12 2008-07-17 Novartis Ag Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
CN104557600A (en) * 2015-01-26 2015-04-29 苏州明锐医药科技有限公司 Preparation method of sacubitril
CN104860894A (en) * 2015-06-10 2015-08-26 北京博全健医药科技有限公司 Method for preparing cardiotonic drug LCZ696
CN105017082A (en) * 2015-07-31 2015-11-04 上海皓元化学科技有限公司 Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4604383A (en) * 1983-07-12 1986-08-05 Societe Anonyme Styled: Sanofi Pyrrolidin-2-ones and medicaments containing them
WO2008031567A1 (en) * 2006-09-13 2008-03-20 Novartis Ag Process for preparing biaryl substituted 4-amino-butyric acid or derivatives thereof and their use in the production of nep inhibitors
WO2008083967A2 (en) * 2007-01-12 2008-07-17 Novartis Ag Process for preparing 5-biphenyl-4-amino-2-methyl pentanoic acid
CN104557600A (en) * 2015-01-26 2015-04-29 苏州明锐医药科技有限公司 Preparation method of sacubitril
CN104860894A (en) * 2015-06-10 2015-08-26 北京博全健医药科技有限公司 Method for preparing cardiotonic drug LCZ696
CN105017082A (en) * 2015-07-31 2015-11-04 上海皓元化学科技有限公司 Preparation method of cardiotonic drug Entresto key intermediate (R)-tert-butyl-(1-([1,1'-biphenyl]-4-yl)-3-hydroxypropane-2-yl)carbamate

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