CN102060732A - 5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof - Google Patents

5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof Download PDF

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CN102060732A
CN102060732A CN2010100039198A CN201010003919A CN102060732A CN 102060732 A CN102060732 A CN 102060732A CN 2010100039198 A CN2010100039198 A CN 2010100039198A CN 201010003919 A CN201010003919 A CN 201010003919A CN 102060732 A CN102060732 A CN 102060732A
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amino
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methoxy propoxy
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邓炳初
吴清泉
潘耀辉
胡兵
张蕾
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Abstract

The invention relates to 5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof, and in particular relates to new 5-amino-4-hydroxy-N-aryl azelamide derivatives shown in the general formula (I) and preparation methods thereof as well as drug compositions containing the derivatives and applications of the derivatives as treatment agents, especially renin inhibitors, and as drugs for treating such diseases related to activity of renin as resistant hypertension, wherein each substituent group in the general formula (I) is as defined in the specification.

Description

5-amino-4-hydroxy-N-aryl azelaoyl amino derivative, its preparation method and in pharmaceutically application
Technical field
The pharmaceutical composition that the present invention relates to a kind of new 5-amino-4-hydroxy-N-aryl azelaoyl amino derivative, its preparation method and contain this derivative with and as therapeutical agent particularly as renin inhibitor with as the purposes with the medicine of renin activity diseases related such as treatment hypertension.
Background technology
Aspartate protease (Aspartic Proteinase) is a class important protein lytic enzyme, participates in the metabolism and the biological regulating and controlling effect of body.In general, their active centre is made up of the catalytic asparagicacid residue of two high conservatives.Common aspartate protease comprises: stomach en-, feritin (Renin), beta-secretase (beta-amyloyd precursor protein lyase, β-site amyloid precursor protein cleaving enzyme, BACE), hiv protease, human T-leukemia virus's proteolytic enzyme etc.Their its generations with numerous disease are relevant, as: in the essential hypertension people, because the katalysis of feritin makes the angiotensin I level raise; Generally believe at present that in addition one of alzheimer's disease main pathogenesis is to form owing to abnormal deposition that BACE acts on the product amyloid beta behind the amyloid precursor protein.In addition, human immunodeficiency virus and human T-leukemia virus all need the participation of aspartate protease separately in its ripening process.
Feritin (Renin), claim Angiotensinogenase again, it is synthetic and release by renal glomerulus, in blood, proangiotensin is cracked into decapeptide angiotensin I (angiotensin I subsequently, Ang I), at angiotensin-converting enzyme (angiotensin converting enzyme, ACE) under the effect, AngI is cracked into octapeptide Angiotensin II (angiotensin II, Ang II), the AngII of high biological activity can shrink direct rising blood pressure by arteries, also can discharge the aldosterone blood pressure that raises indirectly by regulating suprarenal gland.This begins to the regulation mechanism that generates till the aldosterone from feritin, be called renin-angiotensin-aldosterone system (Renin-angiotension-aldosterone system, RAAS).
Renin-angiotensin-aldosterone system (RAAS) is keying action target spot (the Nature Reviews Drug Discovery 2002 such as Zaman M.A. of pharmacological agent cardiovascular system diseases; 1:621-36), the generation and the blocking-up angiotensin-ii receptor of the secretion that it can be by suppressing feritin, activity, prevention Angiotensin II are realized.At present, blocker (the AngiotensinAT1receptor blockers of angiotensin-convertion enzyme inhibitor (ACEi) and angiotensin receptor, ARBS) all go on the market, some medicine becomes antihypertensive a line medicine (Su Dingfeng etc., Chinese Journal of New Drugs and Clinical Remedies 2001; 20 (2) 139-42).But also there are some problems in current ACEi-inhibitor and ABRs, not exclusively block as the non-specific RAAS of the causing system of ACEi, cross high side effect thereby produce as dry cough, headache, blood potassium.Because feritin is directly regulated the initial link in the RAAS system---AngI generates, and vasotonia have high degree of specificity for endogenous, is the research focus that acts on the RASS medicine therefore always.
In addition, by suppressing feritin blocking-up RASS except energy is hypotensive, can also reduce trouble diabetes and other cardiovascular disease risk of causing because of hypertension.As block RAAS and can be used for treating liver, renal fibrosis (Contrib Nephrol.2001 such as Gaedeke J; 135:153-60, World JGastroenterol.2009 such as Regina M.P.; 15 (21): 2579-86), atherosclerosis, myocardial hypertrophy, myocardial fibrosis, diastolic dysfunction, diabetic complication diseases such as (as ephrosis, eye diseases).
First-generation renin inhibitor is a peptide class substrate analogue, and the body internal stability is poor, and action time is short, can only the enteron aisle external administration (people J Biol Chem such as Cumin F, 1985; 260 (16): 9154-57.).After this carry out chemically modified on its basis, synthesized the oral plan peptide of s-generation class renin inhibitor, as CGP-29287, CGP-38560, Rui Mijilun (Remikiren, Ro425892), Yi Najilun (Enalkiren, A64662) (WoodJ M etc., Hypertension, 1985; 7,797-803; Expert Opin Ther Patents2003 such as Maibaum J; 13,589-603; Wood J M etc., J Cardiovasc Pharmacol 1989; 14,221-26).But in the experimentation on animals, its oral administration biaavailability extreme difference (＜2%), the transformation period is short, greatly limits its antihypertensive activity performance, thereby can't be applied to clinical.In recent years, along with the development of medicament research and development technology, design the non-peptide micromolecular of third generation renin inhibitor.Disclosed relevant patent has: WO8805049, EP0678503, WO2004002483, WO2004002957, WO2005051895, WO2005070871, WO2006069788, WO2006103277, WO2007031557 etc.Wherein, the renin inhibitor of having developed at present, because molecular weight is bigger, human bioavailability is low, therefore, improves actively, improves pharmacokinetic property and be the main direction of studying of renin inhibitor from now on.
Purpose of the present invention is exactly to keep the better active while of inhibitor, and the medicine that improves compound is for character, provides a kind of and has feritin and suppress active and can be used for hypertension etc. and the treatment of renin activity diseases related or the clinical medicine of the property alleviated.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide the 5-amino-4-hydroxy N-aryl azelaoyl amino derivative shown in a kind of general formula (I), and their tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt and metabolite or prodrug:
Figure G2010100039198D00021
Wherein:
X is selected from CH or N;
R 1And R 2Be selected from independently of one another hydrogen atom, halogen, alkyl, alkoxyl group or-COR 4, wherein said alkyl or alkoxyl group are optional further to be replaced by one or more substituting groups that are selected from halogen, alkoxyl group, cycloalkyl or Heterocyclylalkyl;
Perhaps, R 1And R 2Coupled atom forms 3～8 yuan of rings together, wherein said 3～8 yuan of rings contain 0～2 two key, contain 0～2 N, O or S (O) n heteroatoms, and described 3～8 yuan of rings are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, alkoxyl group or carbonyl;
R 3Be selected from alkyl or cycloalkyl, wherein said alkyl or cycloalkyl optional further by one or more be selected from alkoxyl group, halogen, hydroxyl, cyano group, cycloalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters substituting group replace;
R 4Be selected from alkyl or aryl;
R 5And R 6Independently be selected from hydrogen atom or alkyl separately;
M is 2 or 3; And
N is 0,1 or 2.
Typical compound of the present invention includes, but are not limited to:
Figure G2010100039198D00041
Figure G2010100039198D00051
Figure G2010100039198D00061
Figure G2010100039198D00071
Figure G2010100039198D00081
Or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt.
The present invention relates to the compound shown in the following general formula (IA), it is as the intermediate of general formula (I) compound:
Figure G2010100039198D00082
Wherein:
X is selected from CH or N;
R 1And R 2Be selected from independently of one another hydrogen atom, halogen, alkyl, alkoxyl group or-COR 4, wherein said alkyl or alkoxyl group are optional further to be replaced by one or more substituting groups that are selected from halogen, alkoxyl group, cycloalkyl or Heterocyclylalkyl;
Perhaps, R 1And R 2Coupled atom forms 3～8 yuan of rings together, wherein said 3～8 yuan of rings contain 0～2 two key, contain 0～2 N, O or S (O) n heteroatoms, and described 3～8 yuan of rings are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, alkoxyl group or carbonyl;
R 4Be selected from alkyl or aryl;
M is 2 or 3;
N is 0,1 or 2; And
PG is the amido protecting group; wherein said amido protecting group is selected from tert-butoxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, formyl radical, p-toluenesulfonyl, trityl, phthalimide-based or 2-xenyl-2-third oxygen carbonyl, is preferably tert-butoxycarbonyl.
The typical compound of the compound shown in the general formula of the present invention (IA) includes, but are not limited to:
Figure G2010100039198D00091
Figure G2010100039198D00101
Figure G2010100039198D00111
The present invention relates to the preparation method of the compound shown in the general formula (IA), this method may further comprise the steps:
Figure G2010100039198D00112
Lactone a is in the presence of catalyzer, and oxidized dose of oxidation obtains compound b;
Wherein said catalyzer is selected from ruthenium chloride, and ruthenium dioxide or ruthenium tetroxide are preferably ruthenium chloride; Described oxygenant is selected from: periodate, hypochlorite, ozone or hydrogen peroxide are preferably periodate;
Figure G2010100039198D00113
Compound b and substituted aromatic amines c reaction obtain general formula compound (IA);
Wherein X, R 1, R 2, m and PG definition such as general formula (IA) described in, and R 7And R 8Independently be selected from hydrogen atom or alkyl separately.
The present invention relates to the compound shown in the following general formula (IB), it is as the intermediate of general formula (I) compound:
Figure G2010100039198D00114
Wherein:
X is selected from CH or N;
R 1And R 2Be selected from independently of one another hydrogen atom, halogen, alkyl, alkoxyl group or-COR 4, wherein said alkyl or alkoxyl group are optional further to be replaced by one or more substituting groups that are selected from halogen, alkoxyl group, cycloalkyl or Heterocyclylalkyl;
Perhaps, R 1And R 2Coupled atom forms 3～8 yuan of rings together, wherein said 3～8 yuan of rings contain 0～2 two key, contain 0～2 N, O or S (O) n heteroatoms, and described 3～8 yuan of rings are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, alkoxyl group or carbonyl;
R 3Be selected from alkyl or cycloalkyl, wherein said alkyl or cycloalkyl optional further by one or more be selected from alkoxyl group, halogen, hydroxyl, cyano group, cycloalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters substituting group replace;
R 4Be selected from alkyl or aryl;
R 5And R 6Independently be selected from hydrogen atom or alkyl separately;
M is 2 or 3;
N is 0,1 or 2; And
G is the silica-based protecting group of hydroxyl, and that the silica-based protecting group of wherein said hydroxyl is selected from is trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, triisopropylsilyl or tert-butyl diphenyl are silica-based.
The present invention relates to the preparation method of the compound shown in the general formula (IB), this method may further comprise the steps:
Figure G2010100039198D00121
Compound d is sloughed prothetic group, obtains Verbindung;
Figure G2010100039198D00122
Verbindung adds diazomethane after generating acyl chlorides under alkaline condition with under thionyl chloride or the phosphorus oxychloride condition, then with silver suboxide, yellow soda ash and Sulfothiorine reaction generate compound f;
Figure G2010100039198D00123
Compound f and substituted aromatic amines c reaction obtain compound g;
The lactonic ring open loop of compound g obtains compound h;
Figure G2010100039198D00132
Compound h and formula R 3NH 2Amine reaction, obtain general formula compound (IB);
Wherein: X, R 1～R 3, m and G definition such as general formula (IB) described in;
Aux is a prothetic group, is selected from the ephedrine derivative, the oxazolidone derivative, and the crassitude ketone derivatives, carbohydrate, cycloalcohol or cyclic amine, described prothetic group preferably includes:
Figure G2010100039198D00133
Another aspect of the present invention relates to the preparation method of general formula (I) compound, and this method may further comprise the steps:
Figure G2010100039198D00134
General formula compound (IA) and formula R 3NH 2Amine reaction, under suitable condition, slough the protecting group PG of amido then, obtain general formula (I) compound;
X wherein, R 1～R 3With described in the definition such as general formula (I) of m, and described in the definition of PG such as the general formula (IA).
Another aspect of the present invention relates to the preparation method of general formula (I) compound, and this method may further comprise the steps:
Figure G2010100039198D00141
Compound (IB) is sloughed the silica-based protecting group G of hydroxyl under suitable condition, then diazo is reduced into amino, obtains general formula (I) compound;
X wherein, R 1～R 3With described in the definition such as general formula (I) of m, and described in the definition of G such as the general formula (IB).
Described pharmaceutically useful salt of the present invention is The compounds of this invention and is selected from following sour formed salt: oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, sulfuric acid, phosphoric acid, citric acid, fumaric acid, acetate or trifluoroacetic acid are preferably fumaric acid.
Another aspect of the present invention relate to The compounds of this invention or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and the purposes of pharmaceutically useful salt in the medicine of preparation renin inhibitor.
Another aspect of the present invention relate to The compounds of this invention or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt as the medicine of renin inhibitor.
The invention still further relates to The compounds of this invention or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt in the medicine of the preparation disease relevant with feritin purposes, wherein relevant with feritin disease comprises: hypertension, atherosclerosis, the instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, infraction back myocardosis, the instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, the complication that diabetes cause is (as ephrosis, vascular disease and neuropathy), coronary artery disease, the restenosis of postangioplasty, eye-chamber pressure raises, glaucoma, the abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dull-witted, anxiety state or cognitive disorders.
Another aspect of the present invention relate to The compounds of this invention or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt as the medicine of the treatment disease relevant with feritin.Wherein with the renin activity diseases associated as mentioned above.
The present invention relates to a kind of method that suppresses feritin, this method comprise the The compounds of this invention of the effective therapeutic dose of patient that needs treatment or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt.
Further, another aspect of the present invention relates to a kind of pharmaceutical composition, its contain the The compounds of this invention for the treatment of effective dose or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt, and pharmaceutically useful carrier or vehicle.This pharmaceutical composition is as the medicine of renin inhibitor.The purposes of this pharmaceutical composition in the medicine of preparation treatment renin inhibitor.This pharmaceutical composition in the medicine of the preparation treatment disease relevant with feritin purposes, wherein relevant with feritin disease comprises: hypertension, atherosclerosis, the instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, infraction back myocardosis, the instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, the complication that diabetes cause is (as ephrosis, vascular disease and neuropathy), coronary artery disease, the restenosis of postangioplasty, eye-chamber pressure raises, glaucoma, the abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dull-witted, anxiety state and cognitive disorders.
Another aspect of the present invention relates to the method for a kind of treatment and renin activity diseases associated, this method comprise the The compounds of this invention of the effective therapeutic dose of patient that needs treatment or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, reach pharmaceutically useful salt or pharmaceutical composition.Wherein with the renin activity diseases associated as mentioned above.
Detailed description of the invention
Unless the phase counter-statement is arranged, otherwise the following term that is used in specification sheets and claims has following implication.
" alkyl " refers to saturated aliphatic hydrocarbon group, comprises the straight chain and the branched group of 1 to 20 carbon atom.The alkyl that preferably contains 1 to 10 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-, the tertiary butyl or amyl group etc.The low alkyl group that more preferably contains 1 to 4 carbon atom, for example methyl, ethyl, propyl group, 2-propyl group, normal-butyl, isobutyl-or the tertiary butyl etc.Alkyl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters.
" cycloalkyl " refers to 3 to 8 yuan of full carbon monocyclic groups, and wherein 3 to 8 yuan of full carbon monocycles can contain one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.For example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenes, hexanaphthene, cyclohexadiene, suberane, cycloheptatriene etc.Cycloalkyl can be replacement or unsubstituted.When being substituted, substituting group is preferably one or more, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters.
" Heterocyclylalkyl " refers to 3 to 8 yuan of monocyclic groups, and one of them or two annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) n (wherein n is 0 to 2 integer), and all the other annular atomses are carbon.These rings can also have one or more pairs of keys, but the none ring has the πDian Zi system of total conjugated.For example pyrrolidyl, piperidino-(1-position only), Piperazino, morpholinyl, thio-morpholinyl, high piperazine its etc., Heterocyclylalkyl can be that replace or unsubstituted.When being substituted, substituting group is preferably one or more, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters.
" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (just share and adjoin the right ring of carbon atom) group, many rings (being its ring that the has phase adjacency pair carbon atom) group with conjugated πDian Zi system.Be preferably 6 to 10 yuan, for example phenyl, naphthyl and anthryl etc.More preferably 6 yuan, phenyl etc. for example.Aryl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters.
" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.It is 5 yuan or 6 yuan of ring heteroaryls that heteroaryl is preferably, for example furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Heteroaryl can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters.
" alkoxyl group " refer to-O-(alkyl) and-O-(unsubstituted cycloalkyl).For example methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be that replace or unsubstituted, and when being substituted, substituting group is preferably one or more, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters.
" aryloxy " refer to-the O-aryl and-the O-heteroaryl, aryl and heteroaryl definition are the same.For example phenoxy group, pyridyloxy, furans oxygen base, thiophene oxy, 2-pyrimidinyl oxy, pyrazine oxygen base etc. and derivative thereof.
The quantity that " 3～8 yuan of cyclic groups " refers to constitute annular atoms is 3～8 yuan, can contain 0～2 pair of key in the ring, and heterocyclic radical contains 0～2 N, O or S (O) n heteroatoms, and remaining annular atoms is a carbon.Be preferably 4～6 yuan of cyclic groups, more preferably 5～6 yuan.3～8 yuan of cyclic groups can be that replace or unsubstituted, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, carbonyl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters.
" hydroxyl " refers to-the OH group.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH 2
" cyano group " refers to-CN.
" nitro " refers to-NO 2
" benzyl " refers to-CH 2-(phenyl).
" tert-butoxycarbonyl " refers to (CH 3) 3O-C (=O)-.
" carbobenzoxy-(Cbz) " refers to (phenyl)-CH 2-C (=O)-
" ethanoyl " refers to CH 3C (=O)-.
" trifluoroacetyl group " refers to CF 3C (=O)-.
" formyl radical " refer to HC (=O)-.
" p-toluenesulfonyl " refers to 4-CH 3-(phenyl)-SO 2-.
" trityl " refers to (phenyl) 3-C-.
" trimethyl silicon based " refers to (CH 3) 3-Si-.
" triethyl is silica-based " refers to (CH 3CH 2) 3-Si-.
" tertiary butyl dimethyl is silica-based " refers to [(CH 3) 3C] (CH 3) 2-Si-.
" triisopropylsilyl " refers to [(CH 3) 3C] 3-Si-.
" tert-butyl diphenyl is silica-based " refers to [(CH 3) 3C] (phenyl) 2-Si-.
" carboxylic acid " refer to-C (=O) OH.
" carboxylicesters " refer to-C (=O) O (alkyl, cycloalkyl, aryl or heteroaryl).
" choose wantonly " or " randomly " mean describe subsequently ground incident or environment can but needn't take place, this explanation comprises that this incident or environment take place or spot occasion not.For example, " the optional heterocyclic group that is replaced by alkyl " mean alkyl can but must not exist, this explanation comprises the situation that situation that heterocyclic group is replaced by alkyl and heterocyclic group are not replaced by alkyl.
" pharmaceutical composition " represent on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components are physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is to promote the administration of compound to organism.
R 4～R 6Definition such as general formula (I) described in.
The synthetic method of The compounds of this invention
In order to finish purpose of the present invention, the present invention adopts following technical scheme:
The preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
Figure G2010100039198D00171
Lactone a is in the presence of catalyzer, and oxidized dose of oxidation obtains compound b;
Wherein said catalyzer is selected from ruthenium chloride, and ruthenium dioxide or ruthenium tetroxide are preferably ruthenium chloride, and described oxygenant is selected from: periodate, hypochlorite, ozone or hydrogen peroxide are preferably periodate;
Intermediate (IA) compound and substituted aromatic amines b reaction obtain amide compound c; Compound c and formula R 3NH 2Amine reaction, under suitable condition, slough the protecting group PG of amine then, obtain general formula (I) compound.
Wherein described in the definition of PG such as the general formula (IA), and X, R 1～R 3With described in the definition such as general formula (I) of m, R 7And R 8Be selected from hydrogen atom or alkyl.
On the other hand, the preparation method of the described compound or its salt of general formula of the present invention (I) may further comprise the steps:
Figure G2010100039198D00181
Compound d is sloughed prothetic group, obtains Verbindung; Verbindung adds diazomethane after generating acyl chlorides under alkaline condition with under the conditions such as thionyl chloride or phosphorus oxychloride, then with silver suboxide, yellow soda ash and Sulfothiorine reaction generate compound f; Compound f and substituted aromatic amines c reaction obtain compound g; The lactonic ring open loop of compound g obtains compound h; Compound h and formula R 3NH 2Amine reaction, obtain general formula (IB) compound; General formula (IB) compound is sloughed the silica-based protecting group G of hydroxyl under suitable condition, then diazo is reduced into amino, obtains general formula (I) compound.
X wherein, R 1～R 3With described in the definition such as general formula (I) of m, and described in the definition of G such as the general formula (IB), Aux is a prothetic group, is selected from the ephedrine derivative, the oxazolidone derivative, and the crassitude ketone derivatives, carbohydrate, cycloalcohol or cyclic amine, described prothetic group preferably includes:
Figure G2010100039198D00182
Embodiment
Be used to further describe the present invention below in conjunction with embodiment, but these embodiment and unrestricted scope of the present invention.
Embodiment
The structure of compound is determined by nucleus magnetic resonance (NMR) and/or mass spectrum (MS).NMR displacement (δ) provides with 1,000,000/(ppm) unit.The mensuration of NMR is to use the BrukerAVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated methanol (CD 3OD), deuterochloroform (CDCl 3), deuterated dimethyl sulfoxide (DMSO-D 6), in be designated as tetramethylsilane (TMS), chemical shift is with 10 -6(ppm) provide as unit.
The mensuration of MS FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Therm, model: FinniganLCQ advantage MAX).
IC 50The mensuration of value is with NovoStar microplate reader (German BMG company).
The tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) is used adopts is 0.15mm～0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm～0.5mm.
Column chromatography generally uses Huanghai Sea silica gel 200～300 order silica gel in Yantai to be carrier.
Starting raw material of the present invention is known, and can buy on market, buys from ABCR GmbH﹠amp; Co.KG, Acros Organics, companies such as Aldrich Chemical Company perhaps can adopt or synthesize according to methods known in the art.
Do not have specified otherwise among the embodiment, reaction is all carried out under argon atmospher or nitrogen atmosphere.
Argon atmospher or nitrogen atmosphere are meant that reaction flask connects an about 1L volumetrical argon gas or nitrogen balloon.
Nitrogen atmosphere is meant that reaction flask connects an about 1L volumetrical hydrogen balloon.
Parr 3916EKX type hydrogenation instrument and clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenation instrument are used in the pressure hydration reaction.
Hydrogenation vacuumizes usually, charges into hydrogen, repeatable operation 3 times.
Microwave reaction uses CEM Discover-S 908860 type microwave reactors.
Do not have specified otherwise among the embodiment, solution is meant the aqueous solution.
Do not have specified otherwise among the embodiment, the temperature of reaction is a room temperature.
Room temperature is optimum temperature of reaction, is preferably 20 ℃～30 ℃.
Tlc is adopted in the monitoring of reaction process among the embodiment, the system of reacting employed developping agent comprises: methylene dichloride and methanol system, normal hexane and ethyl acetate system, sherwood oil and ethyl acetate system, acetone, the volume ratio of solvent is according to different adjusting of polarity of compound.
The system of the eluent of column chromatography comprises: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, the volume ratio of solvent also can add a spot of ammoniacal liquor and acetic acid etc. and regulate according to different adjusting of polarity of compound.
Preparation embodiment:
Embodiment 1
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) azelaoyl amine
Figure G2010100039198D00191
Figure G2010100039198D00201
The first step
3-methoxy-propyl 4-tosylate
Under the ice bath, (45.01g, (252.50g, 2.50mol) in the mixed solvent, (104.80g, 0.55mol), stirring at room was reacted 3 hours to add Tosyl chloride 0.50mol) to be dissolved in 200mL methylene dichloride and triethylamine with 3-methoxyl group-1-propyl alcohol 1a.In reaction solution, add 200mL water, with dichloromethane extraction (150mL * 3), merge organic phase, use saturated sodium bicarbonate solution (50mL * 2), saturated ammonium chloride solution (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 3-methoxy-propyl 4-tosylate 1b (120.01g, light yellow liquid), productive rate: 98.4%.
Second step
4-bromo-1-(3-methoxyl group-propoxy-)-2-nitro-benzene
(10.90g 50.02mmol) is dissolved in 200mLN, in the dinethylformamide with 4-bromo-2-nitrophenols, add 3-methoxy-propyl 4-tosylate 1b (14.64g, 60.01mmol) and Anhydrous potassium carbonate (17.25g, 125.02mmol), 115 ℃ of following stirring reactions 12 hours.In reaction solution, add 200mL water, with ethyl acetate extraction (150mL * 3), merge organic phase, use saturated sodium bicarbonate solution (50mL * 2), saturated ammonium chloride solution (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 4-bromo-1-(3-methoxyl group-propoxy-)-2-nitro-benzene 1c (7.10g, yellow solid), productive rate: 48.9%.
The 3rd step
2-(3-methoxyl group-propoxy-)-aniline
(3.01g 10.01mmol) is dissolved in the 15mL anhydrous methanol, adds palladium/carbon (90mg, 10%), hydrogen exchange three times, stirring reaction 12 hours with 4-bromo-1-(3-methoxyl group-propoxy-)-2-nitro-benzene 1c.Filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 2-(3-methoxyl group-propoxy-)-aniline 1d (1.58g, yellow oil), productive rate: 85.0% with the silica gel column chromatography purifying.MS?m/z(ESI)：182[M+I]
The 4th step
2-cyano group-2-methyl propanamide
With sodium (6.91g 0.30mol) is dissolved in the 250mL dehydrated alcohol, add 2-malonamide nitrile 1e (8.40g, 0.10mol), back flow reaction 2 hours, drip under the room temperature methyl iodide (20mL, 0.40mol), stirring reaction 20 hours.Drip 1M hydrochloric acid and be about 5 to reaction solution pH, concentrating under reduced pressure adds 50mL water, with dichloromethane extraction (150mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, filters, filtrate decompression concentrates, obtain title product 2-cyano group-2-methyl propanamide 1f (7.50g, yellow solid), productive rate: 67.0%.
The 5th step
3-amino-2,2-dimethyl-propionic acid amide
(6.60g 58.90mmol) is dissolved in the 200mL dehydrated alcohol, and (1.40g, 23.85mmol), under 60 ℃, hydrogenation is 4 hours under 2 normal atmosphere to add 50mL ammoniacal liquor and Raney Ni with 2-cyano group-2-methyl propanamide 1f in the hydrogenation bottle.Filter, filtrate decompression concentrates, and obtains title product 3-amino-2,2-dimethyl-propionic acid amide 1g (6.50g, white solid), productive rate: 94.8%.
The 6th step
(3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-(2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid
With (1S, 3S)-3-(4-methoxyl group-3-(3-methoxy propoxy) benzyl)-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-4-methyl amyl carboxylamine tertiary butyl ester 1h (535mg, 1.01mmol, adopt known method Journal ofOrganic Chemistry, 2006,71 (13), 4766-4777 preparation and get) be dissolved in the 3mL acetonitrile, add successively three hydration ruthenium chlorides (6mg, 0.03mmol), sodium periodate (1.72g, 8.02mmol), 3mL tetracol phenixin and 3mL water.Stirring reaction 2.5 hours.Filter, with ethyl acetate extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (385mg, black liquor) crude product, be directly used in the next step.
MS?m/z(ESI)：383[M-1]
The 7th step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (193mg, 0.50mmol) be dissolved in the 10mL acetonitrile, add diisopropylethylamine (0.2mL, 0.50mmol) and benzotriazole-N, N, N ' N '-tetramethyl-urea phosphofluoric acid ester (190mg, 0.50mmol), stirring reaction 10 minutes, add 2-(3-methoxyl group-propoxy-)-aniline 1d (91mg, 0.50mmol), continued stirring reaction 12 hours, back flow reaction 1 hour.The reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 1k (123mg, yellow solid), productive rate: 45.0%.
MS?m/z(ESI)：549[M+I]
1H?NMR(400MHz，d-DMSO，ppm)：δ11.9(br.s，1H)，6.88(d，J＝9.2Hz，1H)，4.32(m，1H)，3.59(m，1H)，2.26～2.12(m，5H)，1.70(m，2H)，1.50～1.20(m，3H)，1.30(s，9H)，0.99～0.70(m，12H)
The 8th step
(3R, 5S, 6S, 8S)-8-((3-amino-2,2-dimethyl-3-oxopropyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 1k (126mg, 0.23mmol) be dissolved in the 1.5mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (80mg, 0.69mmol) and 2 hydroxy pyrimidine (66mg, 0.69mmol), 80 ℃ of following stirring reactions 24 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-((3-amino-2,2-dimethyl-3-oxopropyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 1m (99mg, faint yellow solid), productive rate: 65.0%.
MS?m/z(ESI)：665[M+1]
The 9th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-((3-amino-2,2-dimethyl-3-oxopropyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 1m (100mg, 0.15mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) azelaoyl amine 1 (76mg, faint yellow solid), productive rate: 89.3%.
MS?m/z(ESI)：565[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.24(d，J＝8Hz，1H)，8.16(s，1H)，7.32(br.s，1H)，7.07(t，J＝7.6Hz，1H)，7.02(b?r.s，1H)，6.96(t，J＝7.6Hz，1H)，6.93(d，J＝8.0Hz，1H)，6.86(br.s，1H)，4.18(t，J＝6.2Hz，2H)，3.71(dd，J＝13.2Hz，8Hz，1H)，3.62(m，3H)，3.41(s，3H)，3.15(dd，J＝13.2Hz，4.2Hz，1H)，2.96(br.t，J＝8.0Hz，1H)，2.35～2.49(m，3H)，2.09～2.19(m，3H)，1.54(m，3H)，1.29(s，3H)，0.95(m，15H)
Embodiment 2
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(3-(3-methoxy propoxy) phenyl) azelaoyl amine
Figure G2010100039198D00231
The first step
1-(3-methoxy propoxy)-3-oil of mirbane
With the 3-nitrophenols (2.08g 15.01mmol) is dissolved in the 30mL acetonitrile, add 3-methoxy-propyl 4-tosylate 1b (4.03g, 16.50mmol) and Anhydrous potassium carbonate (6.21g, 45.01mmol), 70 ℃ of following stirring reactions 12 hours.Filter, in filtrate, add the 150mL ethyl acetate, use saturated sodium bicarbonate solution (50mL * 2), saturated ammonium chloride solution (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-(3-methoxy propoxy)-3-oil of mirbane 2a (3.17g, yellow oil) crude product.
Second step
3-(3-methoxyl group-propoxy-) aniline
(3.17g 15.02mmol) is dissolved in the 25mL anhydrous methanol, adds palladium/carbon (310mg, 10%), hydrogen exchange three times, stirring reaction 12 hours, 50 ℃ of stirring reactions 2 hours with 1-(3-methoxy propoxy)-3-oil of mirbane 2a.Filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 3-(3-methoxyl group-propoxy-) aniline 2b (1.40g, red-brown oily matter), productive rate: 51.9% with the silica gel column chromatography purifying.
The 3rd step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(3-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester
Will (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (154mg, 0.40mmol) be dissolved in the 4mL acetonitrile, add diisopropylethylamine (0.16mL, 0.40mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (152mg, 0.40mmol), stirring reaction 10 minutes, (72mg 0.40mmol), continued stirring reaction 22 hours to add 3-(3-methoxyl group-propoxy-) aniline 2b.The reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(3-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 2c (98mg, yellow solid), productive rate: 44.7%.
MS?m/z(ESI)：549[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.30(s，1H)，7.38(s，1H)，7.18(t，J＝8.0Hz，1H)，7.09(d，J＝8Hz，1H)，6.63(br.d，J＝6.8Hz，1H)，4.85(d，J＝10Hz，1H)，4.48(t，J＝7.0Hz，1H)，4.05(t，J＝6.4Hz，2H)，3.85(br.t，J＝10.8Hz，1H)，3.56(t，J＝6.4Hz，2H)，3.34(s，3H)，2.61(m，1H)，2.52(d，J＝12Hz，1H)，1.94～2.28(m，8H)，1.67～1.80(m，2H)，1.46(s，9H)，1.28(m，1H)，1.04(d，J＝6.8Hz，3H)，0.98(d，J＝6.8Hz，3H)，0.92(d，J＝6.8Hz，3H)，0.89(d，J＝6.8Hz，3H)
The 4th step
(3R, 5S, 6S, 8S)-8-((3-amino-2,2-dimethyl-3-oxopropyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(3-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(3-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 2c (96mg, 0.18mmol) be dissolved in the 1mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (61mg, 0.53mmol) and 2 hydroxy pyrimidine (50mg, 0.53mmol), 80 ℃ of following stirring reactions 24 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-((3-amino-2,2-dimethyl-3-oxopropyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(3-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 2d (88mg, yellow solid), productive rate: 75.7%.
MS?m/z(ESI)：665[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.43(s，1H)，7.38(s，1H)，7.20(t，J＝8.0Hz，1H)，7.11(d，J＝8Hz，1H)，6.65(br.d，J＝8.0Hz，1H)，6.53(t，J＝6Hz，1H)，6.11(br.s，1H)，5.56(br.s，1H)，5.15(d，J＝9.2Hz，1H)，4.32(br.s，1H)，4.08(t，J＝6.0Hz，1H)，3.74(d，J＝10.4Hz，1H)，3.53～3.60(m，4H)，3.39(s，3H)，3.32(dd，J＝13.6Hz，6Hz，1H)，2.51(dd，J＝14.4Hz，3.2Hz，1H)，2.26(dd，J＝14.4Hz，9.6Hz，1H)，2.03～2.14(m，3H)，1.88～2.02(m，2H)，1.60～1.88(m，5H)，1.48(s，9H)，1.28(s，6H)，0.98(d，J＝6.8Hz，3H)，0.96(d，.J＝6.4Hz，3H)，0.93(d，J＝6.8Hz，3H)，0.92(d，J＝6.4Hz，3H)
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(3-(3-methoxy propoxy) phenyl) nonane diamide
Under the ice bath, with (3R, 5S, 6S, 8S)-8-((3-amino-2,2-dimethyl-3-oxopropyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(3-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 2d (88mg, 0.13mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.Add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(3-(3-methoxy propoxy) phenyl) azelaoyl amine 2 (59mg, faint yellow solid), productive rate: 79.4%.
MS?m/z(ESI)：565[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ9.32(br.s，1H)，8.2(br.s，2H)，7.56(br.s，1H)，7.34(s，1H)，7.31(br.s，1H)，7.15(m，2H)，6.63(d，J＝6.8Hz，1H)，5.56(b?r.s，1H)，4.05(t，J＝6.0Hz，2H)，3.82(br.t，J＝10Hz，1H)，3.67(br.t，J＝8.8Hz，1H)，3.56(t，J＝6.0Hz，2H)，3.37(s，3H)，3.12(m，1H)，2.99(d，J＝10.8Hz，1H)，2.65(br.d，J＝8.0Hz，1H)，2.46(t，J＝8.8Hz，1H)，2.26(d，J＝8.8Hz，2H)，2.04(m，2H)，1.86(m，4H)，1.49(b?r.t，J＝12Hz，2H)，1.26(m，6H)，0.93(m，12H)
Embodiment 3
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-(trifluoromethyl) phenyl) azelaoyl amine
Figure G2010100039198D00251
The first step
1-(3-methoxy propoxy)-2-nitro-4-(trifluoromethyl) benzene
With 2-nitro-4-(trifluoromethyl) phenol (0.63g, 3.01mmol) be dissolved in the 20mL tetrahydrofuran (THF), add 3-methoxyl group-1-propyl alcohol 1a (308mg, 3.42mmol) and triphenylphosphine (927mg, 3.54mmol), the adding diethyl azodiformate (783mg, 4.50mmol), stirring reaction 4 hours.With the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 1-(3-methoxy propoxy)-2-nitro-4-(trifluoromethyl) benzene 3a (800mg, yellow oil), productive rate 95.6%.
Second step
2-(3-methoxy propoxy)-5-(trifluoromethyl) aniline
With 1-(3-methoxy propoxy)-2-nitro-4-(trifluoromethyl) benzene 3a (800mg 2.86mmol) is dissolved in the 15mL acetonitrile, add iron powder (1.28g, 22.93mmol), dropwise add acetate (3.43g, 57.20mmol), stirring reaction 12 hours.Filter, regulate pH greater than 10,, merge organic phase with ethyl acetate extraction (50mL * 3), water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product 2-(3-methoxy propoxy)-5-(trifluoromethyl) aniline 3b (430mg, yellow oil), productive rate: 6.0%.
The 3rd step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(2-(3-methoxy propoxy)-5-(trifluoromethyl) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (578mg, 1.50mmol) be dissolved in the 10mL methylene dichloride, add triethylamine (1.2mL, 0.90mmol) and oxalyl chloride (194mg, 1.50mmol), stirring reaction 1 hour, concentrating under reduced pressure 1 hour, add again triethylamine (1.2mL, 0.90mmol) and 2-(3-methoxy propoxy)-5-(trifluoromethyl) aniline 3b (374mg, 1.5mmol), stirring reaction 3 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(2-(3-methoxy propoxy)-5-(trifluoromethyl) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 3c (370mg, yellow solid), productive rate: 40.0%.
MS?m/z(ESI)：639[M+23]
The 4th step
(3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-(trifluoromethyl) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(2-(3-methoxy propoxy)-5-(trifluoromethyl) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 3c (142mg, 0.23mmol) be dissolved in the 1.5mL triethylamine, add 4-fluoro-benzylamine (87mg, 0.69mmol) and 2 hydroxy pyrimidine (66mg, 0.69mmol), 80 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-(trifluoromethyl) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 3d (88mg, yellow solid), productive rate: 51.5%.MS?m/z(ESI)：742[M+1]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propyl oxygen
Base)-and 5-(trifluoromethyl) phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(88mg 0.12mmol) is dissolved in the 1mL methylene dichloride 8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-(trifluoromethyl) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 3d, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-(trifluoromethyl) phenyl) azelaoyl amine 3 (12mg, yellow solid), productive rate 15.8%.
MS?m/z(ESI)：642[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.56(s，1H)，8.22(s，1H)，7.52(m，1H)，7.34(m，3H)，7.02(m，3H)，4.55(m，1H)，4.35(m，1H)，4.26(t，J＝6.4Hz，2H)，3.62(m，2H)，3.4(s，3H)，3.15(m，1H)，3.00(m，1H)，2.50～1.70(m，12H)，0.92(m，12H)
Embodiment 4
(2S, 4S, 5S, 7R)-N 1-(4-luorobenzyl)-5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) azelaoyl amine
Figure G2010100039198D00271
The first step
(3R, 5S, 6S, 8S)-8-((4-luorobenzyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 1k (42mg, 0.077mmol) be dissolved in the 1mL triethylamine, add 4-fluoro-benzylamine (29mg, 0.23mmol) and 2 hydroxy pyrimidine (22mg, 0.23mmol), 80 ℃ of following stirring reactions 24 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-((4-luorobenzyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 4a (32mg, yellow solid), productive rate: 62.0%.
MS?m/z(ESI)：674[M+1]
Second step
(2S, 4S, 5S, 7R)-N 1-(4-luorobenzyl)-5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) nonane diamide
Under the ice bath, with (3R, 5S, 6S, 8S)-(32mg 0.048mmol) is dissolved in the 1mL methylene dichloride 8-((4-luorobenzyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 4a, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the system A of suitable proportion) the gained resistates obtains title product (2S, 4S with the thin-layer chromatography purifying, 5S, 7R)-N 1-(4-luorobenzyl)-5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) azelaoyl amine 4 (18mg, yellow solid), productive rate: 66.0%.
MS?m/z(ESI)：573[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.19(d，J＝8Hz，1H)，8.14(br.s，1H)，7.77(br.s，1H)，7.31(m，2H)，7.06(t，J＝8Hz，1H)，6.95(m，4H)，4.54(dd，J＝14.8Hz，5.4Hz，1H)，4.24(br.d，J＝14.4Hz，1H)，4.17(t，J＝6.0Hz，2H)，3.69(m，1H)，3.62(t，J＝5.6Hz，2H)，3.41(s，3H)，3.05(m，1H)，2.25～2.50(m，2H)，2.12(m，3H)，1.60～2.0(m，4H)，1.40～1.58(m，2H)，0.94(m，12H)
Embodiment 5
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl)-N 1-(2-(methane sulfonyl) ethyl) azelaoyl amine
Figure G2010100039198D00281
The first step
(3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl-8-((2-(methane sulfonyl) ethyl) carbamyl)-1-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 1k (42mg, 0.077mmol) be dissolved in the 1mL triethylamine, add 2-sulfonyloxy methyl-ethylamine hydrochloride (37mg, 0.23mmol) and 2 hydroxy pyrimidine (22mg, 0.23mmol), 80 ℃ of following stirring reactions 24 hours.Concentrating under reduced pressure; with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion); obtain title product (3R; 5S; 6S; 8S)-and 6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl-8-((2-(methane sulfonyl) ethyl) carbamyl)-1-oxo decyl-5-aminocarbamic acid tertiary butyl ester 5a (27mg, faint yellow solid), productive rate: 52.0%.
MS?m/z(ESI)：672[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.26(d，J＝8Hz，1H)，8.00(br.s，1H)，7.06(t，J＝8Hz，1H)，6.95(m，2H)，6.49(br.s，1H)，4.98(d，J＝8.8Hz，1H)，4.18(t，J＝6.0Hz，2H)，3.9(m，2H)，3.73(m，2H)，3.62(t，J＝6.0Hz，2H)，3.50(m，1H)，3.41(s，3H)，3.38(m，1H)，3.24(m，1H)，3.0(m，1H)，2.97(s，3H)，2.46(dd，J＝15.2Hz，4.2Hz，1H)，2.31(m，1H)，1.57～2.0(m，7H)，1.45(s，9H)，1.40(m，2H)，0.94(m，12H)
Second step
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl)-N 1-(2-(methane sulfonyl) ethyl) azelaoyl amine
Under the ice bath; with (3R; 5S; 6S; 8S)-(27mg 0.041mmol) is dissolved in the 1mL methylene dichloride 6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl-8-((2-(methane sulfonyl) ethyl) carbamyl)-1-oxo decyl-5-aminocarbamic acid tertiary butyl ester 5a, adds 2mL concentrated hydrochloric acid and 1; 4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH,, merge organic phase with dichloromethane extraction (10mL * 3) greater than 7, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl)-N 1-(2-(methane sulfonyl) ethyl) azelaoyl amine 5 (8mg, yellow solid), productive rate: 35.0%.
MS?m/z(ESI)：572[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.25(d，J＝8Hz，1H)，8.18(br.s，1H)，7.79(s，1H)，7.08(t，J＝8Hz，1H)，6.97(m，2H)，4.20(t，J＝6.0Hz，2H)，3.92(b?r.s，1H)，3.76(br.s，1H)，3.63(t，J＝6.0Hz，2H)，3.45～3.58(m，2H)，3.42(s，3H)，3.06(m，4H)，2.54(br.d，J＝14Hz，1H)，2.27～2.47(m，2H)，2.13(m，3H)，1.57～2.0(m，7H)，1.45(m，1H)，1.40(m，2H)，0.95(m，12H)
Embodiment 6
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl)-N 1-(3, the 5-difluorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00291
Figure G2010100039198D00301
The first step
4-(3-methoxyl group-propoxy-)-3-nitro-phenyl aldehyde
With 4-hydroxyl-3-nitrobenzaldehyde (5.01g, 30.01mmol) be dissolved in the 100mL tetrahydrofuran (THF), add 3-methoxyl group-1-propyl alcohol 1a (3.08g, 34.20mmol) and triphenylphosphine (9.28g, 35.40mmol), the adding diethyl azodiformate (7.84g, 45.02mmol), stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, (eluent: the gained resistates system B of suitable proportion) obtains title product 4-(3-methoxyl group-propoxy-)-3-nitro-phenyl aldehyde 6a (7.17g, yellow solid), productive rate: 99.9% with the silica gel column chromatography purifying.
Second step
Triphenyl cyclopentyl bromination phosphine
With 1-bromo-pentamethylene 6b (5.31g, 35.01mmol) and triphenylphosphine 6c (7.90g 30.02mmol) joins in the reaction flask, 140 ℃ of following back flow reaction 18 hours.Reacting liquid filtering, filtrate decompression concentrates, and obtains title product triphenyl cyclopentyl bromination phosphine 6d (9.97g, white solid), productive rate: 69.5%.
The 3rd step
4-(cyclopentenyl methyl)-1-(3-methoxy propoxy)-2-oil of mirbane
Under-15 ℃, with triphenyl cyclopentyl bromination phosphine 6d (4.6g, 11.25mmol) be dissolved in the 60mL anhydrous tetrahydro furan, drip n-Butyl Lithium (5mL, 11.25mmol), stirring reaction 1 hour adds 4-(3-methoxyl group-propoxy-)-3-nitro-phenyl aldehyde 6a (1.25g, 5.22mmol), continued stirring reaction 2 hours.
Under the ice bath, in reaction solution, add the 30mL saturated ammonium chloride solution, regulate pH greater than 7 with saturated sodium bicarbonate solution, with ethyl acetate extraction (60mL * 3), merge organic phase, water (30mL * 2) and saturated common salt water washing (30mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system A of suitable proportion) obtains title product 4-(cyclopentenyl methyl)-1-(3-methoxy propoxy)-2-oil of mirbane 6e (480mg with the thin-layer chromatography purifying, yellow oil), productive rate: 31.5%.
The 4th step
5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) aniline
(480mg 1.60mmol) is dissolved in the 15mL anhydrous methanol, adds palladium/carbon (90mg, 10%), hydrogen exchange three times, stirring reaction 12 hours with 4-(cyclopentenyl methyl)-1-(3-methoxy propoxy)-2-oil of mirbane 6e.Filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) aniline 6f (315mg with the silica gel column chromatography purifying, yellow oil), productive rate: 75.0%.
MS?m/z(ESI)：264[M+1]
The 5th step
(1S, 3R)-5-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (578mg, 1.50mmol) be dissolved in the 20mL acetonitrile, add diisopropylethylamine (0.75mL, 1.01mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (568mg, 1.50mmol), stirring reaction 10 minutes, (316mg 1.20mmol), continued stirring reaction 18 hours to add 5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) aniline 6f.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-5-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 6g (390mg, yellow solid), productive rate: 41.0%.
MS?m/z(ESI)：631[M+1]
The 6th step
(3R, 5S, 6S, 8S)-1-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-8-(3,5-difluorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 6g (160mg, 0.26mmol) be dissolved in the 1mL triethylamine, add 3, and 5-two fluoro-benzylamines (111mg, 0.77mmol) and 2 hydroxy pyrimidine (74mg, 0.77mmol), 80 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-1-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-8-(3,5-difluorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 6h (98mg, faint yellow solid), productive rate: 50.0%.
MS?m/z(ESI)：796[M+23]
The 7th step
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl)-N 1-(3, the 5-difluorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-1-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-8-(3,5-difluorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 6h (98mg, 0.12mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl)-N 1-(3, the 5-difluorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 6 (25mg, yellow solid), productive rate: 29.3%.
MS?m/z(ESI)：674[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.12(s，1H)，8.01(s，1H)，6.86～6.79(m，5H)，6.66(m，1H)，4.40(m，2H)，4.12(t，J＝6.4Hz，2H)，3.56(t，J＝6.4Hz，2H)，3.38(s，3H)，3.15～3.40(m，2H)，2.70～1.14(m，23H)，0.92(m，12H)
Embodiment 7
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(3-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00321
The-step
1-fluoro-2-(3-methoxy propoxy)-3-oil of mirbane
(314mg 2.01mmol) is dissolved in the 10mL tetrahydrofuran (THF), adds 3-methoxyl group-1-propyl alcohol 1a (206mg with 2-fluoro-6-nitrophenols, 2.28mmol) and triphenylphosphine (618mg, 2.36mmol), adding diethyl azodiformate (522mg, 3.02mmol), stirring reaction 1 hour.The reaction solution concentrating under reduced pressure, (eluent: the gained resistates system B of suitable proportion) obtains title product 1-fluoro-2-(3-methoxy propoxy)-3-oil of mirbane 7a (458mg, yellow oil), productive rate: 99.9% with the silica gel column chromatography purifying.
Second step
3-fluoro-2-(3-methoxy propoxy) aniline
With 1-fluoro-2-(3-methoxy propoxy)-3-oil of mirbane 7a (458mg 2.01mmol) is dissolved in the 20mL acetonitrile, add iron powder (896mg, 16.01mmol), dropwise add acetate (2.40g, 40.02mmol), stirring reaction 12 hours.Filter, add the 1M sodium hydroxide solution and regulate pH greater than 10.With ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 3-fluoro-2-(3-methoxy propoxy) aniline 7b (311mg, brown oily), productive rate: 78.0%.
The 3rd step
(1S, 3R)-5-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (116mg, 0.30mmol) be dissolved in the 10mL methylene dichloride, add triethylamine (0.12mL, 0.090mmol) and oxalyl chloride (38mg, 0.30mmol), stirring reaction 1 hour, concentrating under reduced pressure 1 hour, (0.12mL is 0.090mmol) with 3-fluoro-2-(3-methoxy propoxy) aniline 7b (60mg to add triethylamine again, 0.30mmol), continued stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-5-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 7c (68mg, yellow solid), productive rate: 38.4%.
MS?m/z(ESI)：467[M-100+1]
The 4th step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 7c (68mg, 0.12mmol) be dissolved in the 2mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (34mg, 0.36mmol) and 2 hydroxy pyrimidine (42mg, 0.36mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 7d (29mg, yellow solid), productive rate: 70.0%.
MS?m/z(ESI)：705[M+23]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(3-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 7d (30mg, 0.044mmol) be dissolved in the 1mL methylene dichloride, 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(3-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 7 (20mg, yellow solid), productive rate: 78.0%.
MS?m/z(ESI)：583[M+1]
1H?NMR(400MHz，CD 3OD，ppm)：δ7.78(d，J＝8.0Hz，1H)，7.03(m，1H)，6.94(m，1H)，6.77(m，1H)，6.54(d，J＝8.4Hz，1H)，6.39(m，1H)，6.15(m，1H)，4.17(m，2H)，4.07(t，J＝6.4Hz，2H)，3.51～3.74(m，2H)，3.38(s，3H)，3.25(m，1H)，3.03(m，1H)，2.21～2.50(m，3H)，2.21～1.70(m，6H)，1.40～1.71(m，3H)，1.19(s，6H)，0.92(m，12H)
Embodiment 8
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(4-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00341
The first step
4-fluoro-2-(3-methoxy propoxy)-1-oil of mirbane
With 5-fluoro-2-nitrophenols (314mg, 2.01mmol) and cesium carbonate (1.36g 4.18mmol) is dissolved in 30mL N, in the dinethylformamide, add 3-methoxy-propyl 4-tosylate 1b (369mg, 2.20mmol), stirring reaction 10 hours.With 100mL water washing reaction solution, ethyl acetate extraction (60mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the gained resistates system A of suitable proportion) obtains title product 4-fluoro-2-(3-methoxy propoxy)-1-oil of mirbane 8a (370mg with the thin-layer chromatography purifying, yellow oil), productive rate: 80.0%.
Second step
4-fluoro-2-(3-methoxy propoxy) aniline
With 4-fluoro-2-(3-methoxy propoxy)-1-oil of mirbane 8a (89mg 1.01mmol) is dissolved in the 5mL acetonitrile, add iron powder (450mg, 8.02mmol), dropwise add acetate (1.20g, 20.01mmol), stirring reaction 12 hours.Filter, add the 1M sodium hydroxide solution and regulate pH greater than 10.With ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 4-fluoro-2-(3-methoxy propoxy) aniline 8b (162mg, brown liquid), productive rate: 81.4%.
The 3rd step
(1S, 3R)-5-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (116mg, 0.30mmol) be dissolved in the 10mL methylene dichloride, add triethylamine (0.12mL, 0.090mmol) and oxalyl chloride (38mg, 0.30mmol), stirring reaction 1 hour, concentrating under reduced pressure 1 hour, (0.12mL is 0.090mmol) with 4-fluoro-2-(3-methoxy propoxy) aniline 8b (60mg to add triethylamine again, 0.30mmol), continued stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-5-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 8c (70mg, yellow solid), productive rate: 41.2%.
MS?m/z(ESI)：467[M-100+1]
The 4th step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 8c (70mg, 0.12mmol) be dissolved in the 2mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (43mg, 0.37mmol) and 2 hydroxy pyrimidine (35mg, 0.37mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-and 1-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 8d (32mg, yellow solid), productive rate: 70.0%.
MS?m/z(ESI)：705[M+23]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(4-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 8d (32mg, 0.047mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(4-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 8 (22mg, faint yellow solid), productive rate: 80.5%.
MS?m/z(ESI)：583[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.10(m，1H)，8.01(s，1H)，7.36(b?r.s，1H)，7.02(b?r.s，1H)，6.93(b?r.s，1H)，6.62(m，2H)，4.07(t，J＝6.0Hz，2H)，3.69(dd，J＝13.2Hz，8Hz，1H)，3.56(m，3H)，3.37(s，3H)，3.08(m，1H)，2.95(b?r.s，1H)，2.39(m，3H)，2.14(m，1H)，2.09(m，2H)，1.67～1.95(m，4H)，1.50(t，J＝12Hz，2H)，1.21(s，6H)，0.92(m，12H)
Embodiment 9
(2S, 4S, 5S, 7R)-N 1-(4-luorobenzyl)-5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) pyridin-3-yl) azelaoyl amine
Figure G2010100039198D00361
The first step
2-(3-methoxy propoxy)-3-nitropyridine
(717mg 5.12mmol) is dissolved in 15mL 1, in the 4-dioxane with the 2-hydroxy-3-nitropyridine, add 3-methoxyl group-1-propyl alcohol 1a (496mg, 5.5mmol) and triphenylphosphine (1.52g, 6mmol), the adding diethyl azodiformate (1.04g, 6mmol), stirring reaction 48 hours.With the reaction solution concentrating under reduced pressure, (eluent: the gained resistates system B of suitable proportion) obtains title product 2-(3-methoxy propoxy)-3-nitropyridine 9a (513mg, yellow oily), productive rate: 47.2% with the silica gel column chromatography purifying.
Second step
2-(3-methoxy propoxy) pyridine-3-amine
With 2-(3-methoxy propoxy)-3-nitropyridine 9a (513mg 2.42mmol) is dissolved in the 10mL acetonitrile, add iron powder (1.18g, 21.13mmol), dropwise add acetate (2.90g, 48.4mmol), stirring reaction 48 hours.Filter, add the 1M sodium hydroxide solution and regulate pH greater than 10.With ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2), saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 2-(3-methoxy propoxy) pyridine-3-amine 9b (424mg, blackish green oily), productive rate: 96.4%.
The 3rd step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(2-(3-methoxy propoxy)
Pyridin-3-yl amino)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) (116mg 0.3mmol) is dissolved in 4mL N to valeric acid 1j, in the dinethylformamide, in reaction solution, add successively diethyl phosphorocyanidate (98mg, 0.3mmol) and triethylamine (91mg, 0.3mmol), stirring reaction 10 minutes, (55mg 0.3mmol), continued stirring reaction 13 hours to add 2-(3-methoxy propoxy) pyridine-3-amine 9b.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(2-(3-methoxy propoxy) pyridin-3-yl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 9c (67mg, yellow solid) crude product, productive rate: 40.6%.
MS?m/z(ESI)：550[M+1]
The 4th step
(3R, 5S, 6S, 8S)-8-((4-luorobenzyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) pyridin-3-yl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(2-(3-methoxy propoxy) pyridin-3-yl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 9c (67mg, 0.12mmol) be dissolved in the 2mL triethylamine, add 4-fluoro-benzylamine (46mg, 0.36mmol) and 2 hydroxy pyrimidine (35mg, 0.36mmol), 80 ℃ of following stirring reactions 14 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-((4-luorobenzyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) pyridin-3-yl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 9d (28mg, faint yellow solid), productive rate: 13.9%.
MS?m/z(ESI)：675[M+1]
The 5th step
(2S, 4S, 5S, 7R)-N 1-(4-luorobenzyl)-5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) pyridin-3-yl) azelaoyl amine
Ice bath is down with (3R, 5S, 6S, 8S)-8-((4-luorobenzyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) pyridin-3-yl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 9d (28mg, 0.1mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (10mL * 2) and saturated common salt washing (10mL * 2) is washed successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-N 1-(4-luorobenzyl)-5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) pyridin-3-yl) azelaoyl amine 9 (18mg, yellow solid), productive rate: 75.6%.
MS?m/z(ESI)：575[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.41(d，J＝8Hz，1H)，7.90(s，1H)，7.83(dd，J＝4.8Hz，1.6Hz，1H)，7.27(m，2H)，6.94(m，2H)，6.80(dd，J＝8.0Hz，4.8Hz，1H)，4.48(m，3H)，4.25(dd，J＝14.4Hz，4.8Hz，1H)，3.53(m，3H)，3.35(s，3H)，2.83(br.s，1H)，2.44(dd，J＝16.0Hz，4Hz，1H)，2.30(m，2H)，2.08(m，4H)，1.52～1.91(m，6H)，1.41(m，2H)，0.89(m，12H)
Embodiment 10
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-yl) azelaoyl amine
Figure G2010100039198D00381
The first step
4-nitro-2,3-dihydro-1H-5-indanol
With 2,3-dihydro-1H-5-indanol 10a (2.50g 18.60mmol) is dissolved in the 24mL ether, and the dropping concentrated nitric acid (1.29g, 20.50mmol), stirring reaction 2 hours.Water (50mL * 6), saturated common salt water washing (20mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product 4-nitro-2,3-dihydro-1H-5-indanol 10b (2.80g with the silica gel column chromatography purifying, orange/yellow solid), productive rate: 84.0%.
Second step
3-methoxy-propyl methanesulfonates
Under the ice bath, (54.4mL 0.57mol) is dissolved in 200mL methylene dichloride and triethylamine (158mL with 3-methoxyl group-1-propyl alcohol 1a, 1.14mol) mixing solutions in, add methylsulfonyl chloride (50mL, 0.66mol), stirring reaction 0.5 hour, stirring at room reaction 1 hour.In reaction solution, add 200mL water, with dichloromethane extraction (150mL * 3), merge organic phase, use saturated sodium bicarbonate solution (50mL * 2), saturated ammonium chloride solution (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product 3-methoxy-propyl methanesulfonates 10g (72.99g, light yellow liquid), productive rate: 76.0%.
The 3rd step
5-(3-methoxy propoxy)-4-nitro-2,3-dihydro-1H-indenes
With 4-nitro-2, (1.40g 7.80mmol) is dissolved in the 5mL acetonitrile 3-dihydro-1H-5-indanol 10b, add 3-methoxy-propyl methanesulfonates 10g (1.44g, 8.60mmol) and Anhydrous potassium carbonate (1.62g, 11.70mmol), 100 ℃ of following stirring reactions 6 hours.Filter, in filtrate, add the 150mL ethyl acetate, use saturated sodium bicarbonate solution (50mL * 2), saturated ammonium chloride solution (50mL * 2) and saturated common salt water washing (50mL * 2) successively, anhydrous sodium sulfate drying filters, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product 5-(3-methoxy propoxy)-4-nitro-2,3-dihydro-1H-indenes 10c (1.37g with the silica gel column chromatography purifying, yellow solid) crude product, productive rate: 69.3%.
The 4th step
5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-acid amides
With 5-(3-methoxy propoxy)-4-nitro-2, (370mg 1.47mmol) is dissolved in the 5mL anhydrous methanol 3-dihydro-1H-indenes 10c, adds palladium/carbon (37mg, 10%), hydrogen exchange three times, stirring reaction 12 hours.Filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-acid amides 10d (108mg, brown oil), productive rate: 33.0%.
The 5th step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (116mg, 0.30mmol) be dissolved in the 5mL acetonitrile, add diisopropylethylamine (0.15mL, 0.30mmol) and benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (114mg, 0.30mmol), stirring reaction 10 minutes adds 5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-acid amides 10d (114mg, 0.30mmol), continued stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester 10e (86mg, yellow solid), productive rate: 40.4%.
MS?m/z(ESI)：589[M+1]
The 6th step
(3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester 10e (86mg, 0.073mmol) be dissolved in the 1mL triethylamine, add 4-fluoro-benzylamine (27mg, 0.22mmol) and 2 hydroxy pyrimidine (21mg, 0.22mmol), 80 ℃ of following stirring reactions 15 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 10f (84mg, yellow solid), productive rate: 78.7%.
MS?m/z(ESI)：714[M+1]
The 7th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 10f (84mg, 0.12mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-4-yl) azelaoyl amine 10 (56mg, faint yellow solid), productive rate: 77.6%.
MS?m/z(ESI)：614[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.77(s，1H)，7.66(s，1H)，7.27(m，2H)，7.02(d，J＝8.0Hz，1H)，6.96(m，2H)，6.69(d，J＝8.0Hz，1H)，4.45(dd，J＝14.4Hz，6.0Hz，1H)，4.21(dd，J＝14.4Hz，4.8Hz，1H)，4.06(br.s，2H)，3.54(m，3H)，3.36(s，3H)，2.92(m，2H)，2.82(t，J＝7.2Hz，2H)，2.77(t，J＝7.2Hz，2H)，2.38(m，3H)，1.93～2.24(m，6H)，1.84(m，4H)，1.68(m，1H)，1.42(m，1H)，0.93(m，12H)
Embodiment 11
(2S, 4S, 5S, 7R)-5-amino-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
The first step
The 4-tertiary butyl-1-(3-methoxy propoxy)-2-oil of mirbane
With the 4-tertiary butyl-2-nitrophenols (1.46g, 7.50mmol) be dissolved in the 50mL tetrahydrofuran (THF), add 3-methoxyl group-1-propyl alcohol 1a (1.01g, 11.25mmol) and triphenylphosphine (2.95g, 11.25mmol), the adding diethyl azodiformate (1.96g, 11.25mmol), stirring reaction 4 hours.With the reaction solution concentrating under reduced pressure, (eluent: the gained resistates system B of suitable proportion) obtains the title product 4-tertiary butyl-1-(3-methoxy propoxy)-2-oil of mirbane 11a (1.85g, colourless liquid), productive rate: 92.5% with the silica gel column chromatography purifying.MS?m/z(ESI)：268[M+1]
Second step
The 5-tertiary butyl-2-(3-methoxy propoxy) aniline
(1.01g 3.70mmol) is dissolved in the 30mL ethanol, adds palladium/carbon (200mg, 10%), hydrogen exchange three times, stirring reaction 12 hours with the 4-tertiary butyl-1-(3-methoxy propoxy)-2-oil of mirbane 11a.Filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains the title product 5-tertiary butyl-2-(3-methoxy propoxy) aniline 11b (805mg, colourless liquid), productive rate 90.7% with the silica gel column chromatography purifying.
MS?m/z(ESI)：238[M+1]
The 3rd step
(1S, 3R)-5-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (154mg, 0.40mmol) be dissolved in the 4mL acetonitrile, add diisopropylethylamine (0.2mL, 0.40mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (227mg, 0.60mmol), stirring reaction 10 minutes, (190mg 0.80mmol), continued stirring reaction 12 hours to add the 5-tertiary butyl-2-(3-methoxy propoxy) aniline 11b.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-5-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 11c (151mg, faint yellow oily), productive rate: 62.6%.
MS?m/z(ESI)：605[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：88.39(s，1H)，7.84(s，1H)，7.01(dd，J＝8.0Hz，4.0Hz，1H)，6.81(d，J＝4.0Hz，1H)，4.53(m，2H)，4.11(t，J＝8.0Hz，2H)，3.87(m，1H)，3.57(t，J＝8.0Hz，1H)，3.36(s，3H)，2.55(m，1H)，2.38(m，2H)，2.20～2.07(m，5H)，1.93(m，2H)，1.71(m，1H)，1.50(m，1H)，1.42(s，9H)，1.30(s，9H)，1.00(d，J＝8.0Hz，3H)，0.94(d，J＝8.0Hz，3H)，0.93(d，J＝8.0Hz，3H)，0.90(d，J＝8.0Hz，3H)
The 4th step
(3R, 5S, 6S, 8S)-1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 11c (151mg, 0.25mmol) be dissolved in the 5mL triethylamine, add 4-fluoro-benzylamine (94mg, 0.75mmol) and 2 hydroxy pyrimidine (71mg, 0.75mmol), 80 ℃ of following stirring reactions 15 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 11d (128mg, colourless thickness), productive rate: 82.0%.
MS?m/z(ESI)：752[M+23]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(128mg 0.18mmol) is dissolved in the 1mL methylene dichloride 1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 11d, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 11 (56mg, faint yellow solid), productive rate: 77.6%.
MS?m/z(ESI)：630[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.27(d，J＝2.4Hz，1H)，8.06(s，1H)，7.56(m，1H)，7.28(dd，J＝8.0Hz，5.6Hz，2H)，7.05(dd，J＝8.8Hz，1.6Hz，1H)，6.95(t，J＝8Hz，2H)，6.82(d，J＝8.8Hz，1H)，4.51(dd，J＝14.4Hz，6.4Hz，1H)，4.23(dd，J＝14.4Hz，4Hz，1H)，4.12(t，J＝6.0Hz，2H)，3.72(t，J＝8.4Hz，1H)，3.57(t，J＝6.0Hz，2H)，3.37(s，3H)，2.94(m，1H)，2.48(m，1H)，2.40(t，J＝8.8Hz，1H)，2.25(dd，J＝16Hz，6.4Hz，1H)，2.07(m，3H)，1.70～2.02(m，4H)，1.38～1.66(m，2H)，1.27(s，9H)，0.88～0.93(m，12H)
Embodiment 12
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine
Figure G2010100039198D00431
The first step
1-(3-methoxy propoxy)-4-methyl-2-oil of mirbane
With 4-methyl-2-nitrophenols (1.01g 6.53mmol) is dissolved in the 30mL acetonitrile, add 3-methoxy-propyl methanesulfonates 10g (0.65g, 7.18mmol) and Anhydrous potassium carbonate (2.70g, 19.59mmol), 70 ℃ of following stirring reactions 12 hours.Filter, in filtrate, add the 150mL ethyl acetate, use saturated sodium bicarbonate solution (50mL * 2), saturated ammonium chloride solution (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 1-(3-methoxy propoxy)-4-methyl-2-oil of mirbane 12a (681mg, orange red spicule) crude product.
Second step
2-(3-methoxy propoxy)-5-monomethylaniline
(681mg 3.02mmol) is dissolved in the 10mL anhydrous methanol, adds palladium/carbon (34mg, 10%), hydrogen exchange three times, stirring reaction 12 hours with 1-(3-methoxy propoxy)-4-methyl-2-oil of mirbane 12a.Filter, filtrate decompression concentrates, and obtains title product 2-(3-methoxy propoxy)-5-monomethylaniline 12b (474mg, brown oil), productive rate: 80.5%.
The 3rd step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (115mg, 0.30mmol) be dissolved in the 5mL acetonitrile, add diisopropylethylamine (0.15mL, 0.30mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (114mg, 0.30mmol), stirring reaction 10 minutes, (59mg 0.30mmol), continued stirring reaction 12 hours to add 2-(3-methoxy propoxy)-5-monomethylaniline 12b.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 12c (75mg, yellow solid), productive rate: 44.4%.
MS?m/z(ESI)：563[M+1]
The 4th step
(3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 12c (138mg, 0.25mmol) be dissolved in the 1.5mL triethylamine, add 4-fluoro-benzylamine (92mg, 0.74mmol) and 2 hydroxy pyrimidine (70mg, 0.74mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 12d (97mg, faint yellow solid), productive rate: 57.3%.MS?m/z(ESI)：710[M+23]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(97mg 0.14mmol) is dissolved in the 1mL methylene dichloride 8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 12d, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine 12 (69mg, faint yellow solid), productive rate: 83.3%.
MS?m/z(ESI)：588[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.04(dd，J＝8.8Hz，1.6Hz，2H)，7.41(br.s，1H)，7.28(dd，J＝8.4Hz，5.6Hz，2H)，6.96(t，J＝8.8Hz，2H)，6.80(m，2H)，4.51(dd，J＝14.4Hz，6.4Hz，1H)，4.26(dd，J＝14.4Hz，4.8Hz，1H)，4.11(t，J＝6.4Hz，2H)，3.62(t，J＝8Hz，1H)，3.58(t，J＝6.4Hz，2H)，3.37(s，3H)，2.87(n，1H)，2.46(m，1H)，2.37(m，1H)，2.25(m，1H)，2.24(s，3H)，2.07(m，3H)，1.70～1.95(m，4H)，1.38～1.66(m，2H)，0.88～0.93(m，12H)
Embodiment 13
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine
Figure G2010100039198D00451
The first step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 12c (138mg, 0.25mmol) be dissolved in the 1.5mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (86mg, 0.74mmol) and 2 hydroxy pyrimidine (70mg, 0.74mmol), 80 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 13a (65mg, yellow solid) crude product.
MS?m/z(ESI)：679[M+1]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 13a (66mg, 0.097mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine 13 (36mg, faint yellow solid), productive rate: 64.3%.
MS?m/z(ESI)：579[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.08(s，1H)，8.04(s，1H)，7.11(b?r.s，1H)，6.89(b?r.s，1H)，6.80(m，3H)，4.11(t，J＝6.4Hz，2H)，3.66(dd，J＝14.0Hz，8.0Hz，1H)，3.57(m，3H)，3.37(s，3H)，3.17(dd，J＝13.6Hz，4Hz，1H)，2.88(m，1H)，2.45～2.34(m，3H)，2.27(s，3H)，2.13(m，1H)，2.07(m，2H)，1.70～1.90(m，4H)，1.38～1.58(m，2H)，1.22(s，6H)，0.88～0.95(m，12H)
Embodiment 14
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine fumarate
Figure G2010100039198D00461
The first step
4-methoxyl group-1-(3-methoxy propoxy)-2-oil of mirbane
(338mg 2.01mmol) is dissolved in the 10mL tetrahydrofuran (THF), adds 3-methoxyl group-1-propyl alcohol 1a (206mg with 4-methoxyl group-2-nitrophenols, 2.28mmol) and triphenylphosphine (618mg, 2.36mmol), adding diethyl azodiformate (522mg, 3.02mmol), stirring reaction 1 hour.With the reaction solution concentrating under reduced pressure, (eluent: the gained resistates system B of suitable proportion) obtains title product 4-methoxyl group-1-(3-methoxy propoxy)-2-oil of mirbane 14a (286mg, yellow oil), productive rate: 61.9% with the silica gel column chromatography purifying.
Second step
5-methoxyl group-2-(3-methoxy propoxy) aniline
(286mg 1.24mmol) is dissolved in the 10mL ethanol, adds palladium/carbon (200mg, 10%), hydrogen exchange three times, stirring reaction 12 hours with 4-methoxyl group-1-(3-methoxy propoxy)-2-oil of mirbane 14a.Filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 5-methoxyl group-2-(3-methoxy propoxy) aniline 14b (250mg, purple oily matter) crude product with the silica gel column chromatography purifying.
The 3rd step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (154mg, 0.80mmol) be dissolved in the 15mL acetonitrile, add diisopropylethylamine (0.2mL, 0.40mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (190mg, 0.50mmol), stirring reaction 10 minutes, (193mg 0.50mmol), continued stirring reaction 8 hours to add 5-methoxyl group-2-(3-methoxy propoxy) aniline 14b.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 14c (152mg, yellow solid) crude product.
MS?m/z(ESI)：579[M+1]
The 4th step
(3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 14c (152mg, 0.26mmol) be dissolved in the 1.5mL triethylamine, add 4-fluoro-benzylamine (99mg, 0.78mmol) and 2 hydroxy pyrimidine (75mg, 0.78mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 14d (112mg, yellow solid), productive rate: 60.6%.
MS?m/z(ESI)：704[M+23]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(112mg 0.16mmol) is dissolved in the 1mL methylene dichloride 8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 14d, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine 14 (60mg, yellow solid), productive rate: 62.5%.
MS?m/z(ESI)：604[M+1]
The 6th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine fumarate
Will (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9(60mg 0.10mmol) is dissolved in the 2mL methyl alcohol-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine 14e, and (6mg, 0.050mmol) stirring reaction is 10 minutes to add fumaric acid.The reaction solution concentrating under reduced pressure, obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine fumarate 14 (65mg, faint yellow solid), productive rate: 98.5%.
MS?m/z(ESI)：604[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.16(s，1H)，7.90(d，J＝2.8Hz，1H)，7.50(br.s，1H)，7.29(m，2H)，6.95(t，J＝8.4Hz，2H)，6.82(d，J＝8.8Hz，1H)，6.55(dd，J＝8.8Hz，2.8Hz，1H)，4.49(dd，J＝14.8Hz，2.4Hz，1H)，4.24(dd，J＝14.8Hz，2.2Hz，1H)，4.08(t，J＝6.0Hz，2H)，3.71(s，3H)，3.66(m，1H)，3.57(t，J＝6.0Hz，2H)，3.35(s，3H)，2.90(m，1H)，2.47(dd，J＝16.4Hz，2.4Hz，1H)，2.37(t，J＝9.6Hz，1H)，2.23(dd，J＝16.4Hz，8.0Hz?s，1H)，2.07(m，3H)，1.70～1.96(m，4H)，1.63(m，1H)，1.46(m，1H)，0.88～0.95(m，12H)
Embodiment 15
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine
Figure G2010100039198D00481
The first step
(3R, 5S, 6S, 8S)-8-(3-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 12c (66mg, 0.12mmol) be dissolved in the 1.5mL triethylamine, add 3-fluoro-benzylamine (44mg, 0.35mmol) and 2 hydroxy pyrimidine (34mg, 0.35mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-(3-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 15a (56mg, yellow solid), productive rate: 70.0%.
MS?m/z(ESI)：689[M+1]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propyl oxygen
Base)-and the 5-aminomethyl phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(56mg 0.08mmol) is dissolved in the 1mL methylene dichloride 8-(3-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 15a, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine 15 (27mg, yellow solid), productive rate: 56.5%.
MS?m/z(ESI)：588[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.09(s，1H)，8.00(s，1H)，7.78(br.s，1H)，7.23(m，1H)，7.09(d，J＝8.0Hz，1H)，6.99(d，J＝10Hz，1H)，6.82(m，3H)，4.54(dd，J＝14.8Hz，6.4Hz，1H)，4.24(dd，J＝14.8Hz，4.8Hz，1H)，4.10(t，J＝6.4Hz，2H)，3.67(m，1H)，3.57(t，J＝6.4Hz，2H)，3.37(s，3H)，2.98(m，1H)，2.45(m，2H)，2.28(m，1H)，2.24(s，3H)，2.06(m，4H)，1.55～2.0(m，6H)，1.35～1.54(m，2H)，0.89～0.93(m，12H)
Embodiment 16
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00491
The first step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 11c (111mg, 0.18mmol) be dissolved in the 5mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (63mg, 0.54mmol) and 2 hydroxy pyrimidine (51mg, 0.54mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 16a (75mg, yellow solid), productive rate: 56.8%.
MS?m/z(ESI)：721[M+1]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 16a (75mg, 0.10mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 16 (53mg, white solid), productive rate 82.8%.
MS?m/z(ESI)：621[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.27(d，J＝1.6Hz，1H)，8.09(s，1H)，7.39(br.s，1H)，7.17(br.s，1H)，7.12(br.s，1H)，7.05(d，J＝8.8Hz，1H)，6.82(d，J＝8.4Hz，1H)，4.12(t，J＝6.0Hz，2H)，3.75(dd，J＝14.4Hz，8.8Hz，1H)，3.68(t，J＝9.6Hz，1H)，3.48(s，2H)，3.37(s，3H)，3.04(dd，J＝12.8Hz，4.0Hz，2H)，2.26～2.58(m，3H)，1.69～2.24(m，8H)，1.54(m，2H)，1.27(s，9H)，1.22(s，6H)，0.89～0.95(m，12H)
Embodiment 17
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-chloro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00501
The first step
4-chloro-1-(3-methoxy propoxy)-2-oil of mirbane
(347mg 2.01mmol) is dissolved in the 10mL tetrahydrofuran (THF), adds 3-methoxyl group-1-propyl alcohol 1a (206mg with 4-chloro-2-nitrophenols, 2.28mmol) and triphenylphosphine (618mg, 2.36mmol), adding diethyl azodiformate (522mg, 3.02mmol), stirring reaction 1 hour.With the reaction solution concentrating under reduced pressure, (eluent: the gained resistates system B of suitable proportion) obtains title product 4-chloro-1-(3-methoxy propoxy)-2-oil of mirbane 17a (491mg, yellow oil), productive rate: 99.9% with the silica gel column chromatography purifying.
Second step
5-chloro-2-(3-methoxy propoxy) aniline
With 4-chloro-1-(3-methoxy propoxy)-2-oil of mirbane 17a (490mg 2.01mmol) is dissolved in the 10mL acetonitrile, add iron powder (896mg, 16.02mmol), dropwise add acetate (2.40g, 40.01mmol), stirring reaction 12 hours.Filter, add the 1M sodium hydroxide solution and regulate pH greater than 10.With ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2), saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 5-chloro-2-(3-methoxy propoxy) aniline 17b (335mg, orange oily), productive rate: 77.9%.
The 3rd step
(1S, 3R)-5-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (116mg, 0.30mmol) be dissolved in the 10mL methylene dichloride, add triethylamine (0.12mL, 0.090mmol) and oxalyl chloride (38mg, 0.30mmol), stirring reaction 1 hour, concentrating under reduced pressure 1 hour, (0.12mL is 0.090mmol) with 5-chloro-2-(3-methoxy propoxy) aniline 17b (65mg to add triethylamine again, 0.30mmol), continued stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-5-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 17c (70mg, yellow solid), productive rate: 40%.
MS?m/z(ESI)：483[M-100+1]。
The 4th step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 17c (60mg, 0.10mmol) be dissolved in the 1.5mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (36mg, 0.31mmol) and 2 hydroxy pyrimidine (29mg, 0.31mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 17d (60mg, yellow oil), productive rate: 83%.MS?m/z(ESI)：700[M+1]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-chloro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 17d (50mg, 0.085mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-chloro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 17 (25mg, yellow powder), productive rate: 50.0%.
MS?m/z(ESI)：598[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.19(s，1H)，8.09(d，J＝9.6Hz，1H)，6.93(br.s，1H)，6.80(m，1H)，6.69(m，1H)，6.43(m，1H)，4.11(t，J＝6.0Hz，2H)，3.64(m，1H)，3.59(t，J＝6.0Hz，2H)，3.49(m，1H)，3.36(s，3H)，3.18(m，1H)，2.81(br.s，1H)，2.44(dd，J＝17.6Hz，4.8Hz，1H)，2.32(m，2H)，1.97～2.21(m，3H)，1.80(m，3H)，1.38～1.71(m，4H)，1.22(s，6H)，0.92(m，12H)
Embodiment 18
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
The first step
4-fluoro-1-(3-methoxy propoxy)-2-oil of mirbane
With 4-fluoro-2-nitrophenols (628mg, 4.01mmol) and cesium carbonate (2.60g 2.36mmol) is dissolved in the anhydrous N of 30mL, in N '-dimethyl formamide, add 3-methoxy-propyl 4-tosylate 1b (1.17g, 4.80mmol), 80 ℃ of following stirring reactions 20 hours.With 100mL water washing reaction solution, ethyl acetate extraction (60mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the gained resistates system A of suitable proportion) obtains title product 4-fluoro-1-(3-methoxy propoxy)-2-oil of mirbane 18a (865mg with the thin-layer chromatography purifying, yellow oil), productive rate: 94.4%.
Second step
5-fluoro-2-(3-methoxy propoxy) aniline
With 4-fluoro-1-(3-methoxy propoxy)-2-oil of mirbane 18a (398mg 1.73mmol) is dissolved in the 10mL acetonitrile, add iron powder (778mg, 13.90mmol), dropwise add acetate (2.08g, 34.60mmol), stirring reaction 12 hours.Filter, add the 1M sodium hydroxide solution and regulate pH greater than 10.With ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 5-fluoro-2-(3-methoxy propoxy) aniline 18b (333mg, yellow oily), productive rate: 96.9%.
The 3rd step
(1S, 3R)-5-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (116mg, 0.30mmol) be dissolved in the 10mL methylene dichloride, add triethylamine (0.12mL, 0.90mmol) and oxalyl chloride (38mg, 0.30mmol), stirring reaction 1 hour, concentrating under reduced pressure 1 hour, (0.12mL is 0.90mmol) with 5-fluoro-2-(3-methoxy propoxy) aniline 18b (60mg to add triethylamine again, 0.30mmol), continued stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-5-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 18c (70mg, yellow solid), productive rate: 40.0%.
MS?m/z(ESI)：467[M-100+1]
The 4th step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 18c (70mg, 0.12mmol) be dissolved in the 1.5mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (43mg, 0.36mmol) and 2 hydroxy pyrimidine (34mg, 0.36mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 18d (50mg, faint yellow oily thing), productive rate: 62.0%.
MS?m/z(ESI)：683[M+1]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 18d (50mg, 0.075mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 18 (28mg, yellow powder), productive rate: 56.0%.
MS?m/z(ESI)：599[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.25(s，1H)，8.13(s，1H)，7.28(b?r.s，1H)，6.96(m，3H)，6.77(d，J＝8.8Hz，1H)，4.11(t，J＝6.0Hz，2H)，3.71(dd，J＝14.0Hz，8.0Hz，1H)，3.61(m，1H)，3.57(t，J＝6.0Hz，2H)，3.37(s，3H)，3.09(m，1H)，2.98(b?r.s，1H)，2.41(m，3H)，2.17(m，1H)，2.08(m，2H)，1.83(m，4H)，1.51(m，2H)，1.22(s，6H)，0.92(m，12H)
Embodiment 19
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-nitro-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine
Figure G2010100039198D00541
The first step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 14c (250mg, 0.43mmo1) be dissolved in the 2mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (150mg, 1.30mmo1) and 2 hydroxy pyrimidine (124mg, 1.30mmo1), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 19a (140mg, yellow solid), productive rate: 46.7%.
MS?m/z(ESI)：695[M+1]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-nitro-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(5-methoxyl group-2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 19a (140mg, 0.22mmo1) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-nitro-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(5-methoxyl group-2-(3-methoxy propoxy) phenyl) azelaoyl amine 19 (31mg, yellow powder), productive rate: 26.0%.
MS?m/z(ESI)：595[M+1]
1H?NMR(400MHz，CDCl 3，ppn)：δ8.20(s，1H)，7.92(d，J＝2.8Hz，1H)，7.42(b?r.s，1H)，7.07(br.s，1H)，7.02(br.s，1H)，6.80(d，J＝9.2Hz，1H)，6.55(dd，J＝8.8Hz，3.2Hz，1H)，4.07(t，J＝6.4Hz，2H)，3.73(s，3H)，3.69(m，1H)，3.61(m，1H)，3.58(t，J＝6.0Hz，2H)，3.36(s，3H)，3.08(dd，J＝14.0Hz，4.8Hz，1H)，2.99(m，1H)，2.41(m，3H)，2.14(m，1H)，2.05(m，2H)，1.70～11.95(m，4H)，1.51(m，2H)，1.22(s，6H)，0.92(m，12H)
Embodiment 20
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Figure G2010100039198D00561
The-step
6-nitro-2,3-dihydro-1H-5-indanol
With 2,3-dihydro-1H-5-indanol 10a (2.50g 18.60mmo1) is dissolved in the 24mL ether, and the dropping concentrated nitric acid (1.29g, 20.50mmo1), stirring reaction 2 hours.Water (50mL * 6) and saturated common salt water washing (20mL * 2) successively, anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product 6-nitro-2,3-dihydro-1H-5-indanol 20a (2.80g with the silica gel column chromatography purifying, orange/yellow solid), productive rate: 84.0%.
Second step
5-(3-methoxy propoxy)-6-nitro-2,3-dihydro-1H-indenes
With 6-nitro-2, (1.41g 7.80mmol) is dissolved in the 5mL acetonitrile 3-dihydro-1H-5-indanol 20a, add 3-methoxy-propyl methanesulfonates 10g (1.44g successively, 8.60mmol) and Anhydrous potassium carbonate (1.62g, 11.70mmol), 100 ℃ of following stirring reactions 6 hours.Filter, in filtrate, add the 150mL ethyl acetate, use saturated sodium bicarbonate solution (50mL * 2), saturated ammonium chloride solution (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product 5-(3-methoxy propoxy)-6-nitro-2,3-dihydro-1H-indenes 20b (1.37g with the silica gel column chromatography purifying, yellow solid) crude product, productive rate: 69.3%.
The 3rd step
6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-acid amides
With 5-(3-methoxy propoxy)-6-nitro-2,3-dihydro-1H-indenes 20b (630mg 2.60mmol) is dissolved in the 15mL acetonitrile, add iron powder (1.17g, 20.80mmol), dropwise add acetate (3.12g, 52.02mmol), stirring reaction 12 hours.Filter, add the 1M sodium hydroxide solution and regulate pH greater than 10.With ethyl acetate extraction (50mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, filters, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product 6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-acid amides 20c (79mg with the silica gel column chromatography purifying, yellow oily), productive rate: 4.1%.
MS?m/z(ESI)：222[M+1]
The 4th step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (116mg, 0.30mmo1) be dissolved in the 5mL acetonitrile, add diisopropylethylamine (0.15mL, 0.30mmol) and benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (114mg, 0.30mmol), stirring reaction 10 minutes adds 6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-acid amides 20c (66mg, 0.30mmol), continued stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester 20d (84mg, yellow oil), productive rate: 48.0%.
MS?m/z(ESI)：589[M+1]
The 5th step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-(84mg 0.14mmol) is dissolved in the 1.5mL triethylamine 5-oxo amyl group carboxylamine tertiary butyl ester 20d, adds 3-amino-2,2-dimethyl-propionic acid amide 1g (50mg, 0.43mmol) and 2 hydroxy pyrimidine (22mg, 0.43mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 20e (42mg, yellow oil), productive rate: 55.3%.
MS?m/z(ESI)：705[M+1]
The 6th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-(42mg 0.060mmol) is dissolved in the 1mL methylene dichloride 9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 20e, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (10mL * 2), saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 20 (26mg, yellow solid), productive rate: 72.0%.
MS?m/z(ESI)：605[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.06(s，1H)，8.04(s，1H)，7.27(br.s，1H)，6.98(br.s，1H)，6.78(m，2H)，4.10(t，J＝6.0Hz，2H)，3.65(m，1H)，3.57(t，J＝5.6Hz，2H)，3.37(s，3H)，3.13(dd，J＝4.8Hz，12.4Hz，1H)，2.90(m，1H)，2.83(m，4H)，2.42～2.29(m，3H)，2.14～2.01(m，6H)，1.86～1.71(m，4H)，1.54～1.46(m，2H)，1.22(s，3H)，1.21(s，3H)，0.93～0.89(m，12H)
Embodiment 21
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine fumarate
Figure G2010100039198D00581
The first step
(3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester 20d (108mg, 0.18mmol) be dissolved in the 2mL triethylamine, add 4-fluoro-benzylamine (69mg, 0.55mmol) and 2 hydroxy pyrimidine (53mg, 0.55mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 21a (98mg, yellow solid), productive rate: 75.0%.
MS?m/z(ESI)：714[M+1]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 21a (98mg, 0.14mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1, and 4-dioxane mixing solutions (V/V=1: 1), stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 21b (65mg, yellow solid), productive rate: 77.4%.MS?m/z(ESI)：614[M+1]
The 3rd step
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine fumarate
Will (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9(61mg 0.10mmol) is dissolved in the 2mL methyl alcohol-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 21b, and (6mg, 0.050mmol) stirring reaction is 10 minutes to add fumaric acid.The reaction solution concentrating under reduced pressure, obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine fumarate 21 (65mg, faint yellow solid), productive rate: 97.0%.
MS?m/z(ESI)：614[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.03(s，1H)，8.02(s，1H)，7.51(b?r.s，1H)，7.27(m，2H)，6.94(t，J＝8.8Hz，2H)，6.78(s，1H)，4.70(dd，J＝14.8Hz，6.4Hz，1H)，4.23(dd，J＝14.4Hz，3.2Hz，1H)，4.10(t，J＝6.0Hz，2H)，3.56(t，J＝5.6Hz，3H)，3.36(s，3H)，2.89(s，1H)，2.81(m，4H)，2.36(m，2H)，2.24(dd，J＝16.0Hz，7.2Hz，1H)，2.05(m，5H)，1.75(m，4H)，1.63(t，J＝11.2Hz，1H)，1.43(t，J＝12.0Hz，1H)，0.91(m，12H)
Embodiment 22
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((S)-2-methoxyl group-1-phenylethyl)-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Figure G2010100039198D00591
The first step
(S)-2-amino-2-phenylacetic acid carbethoxy hydrochloride
Under the ice bath, with (S)-2-amino-2-phenylacetic acid 22a (3.02g 20.01mmol) is dissolved in the 35mL dehydrated alcohol, drip thionyl chloride (2.40mL, 30.01mmol), back flow reaction 2 hours.The reaction solution concentrating under reduced pressure obtains title product (S)-2-amino-2-phenylacetic acid carbethoxy hydrochloride 22b (4.70g, white solid) crude product, directly carries out next step reaction.
Second step
(S)-2-(tertiary butyl oxygen carbonylamino)-2-phenylacetic acid ethyl ester
Under the ice bath, (4.70g 20mmol) is dissolved in the 45mL saturated sodium bicarbonate solution, adds 25mL two dimethyl dicarbonate butyl ester (6.54g with (S)-2-amino-2-phenylacetic acid carbethoxy hydrochloride 22b, dichloromethane solution 30mmol), stirring at room reaction 12 hours.With dichloromethane extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (S)-2-(tertiary butyl oxygen carbonylamino)-2-phenylacetic acid ethyl ester 22c (6.01g, colourless liquid) crude product directly carries out next step reaction.
MS?m/z(ESI)：280[M+1]
The 3rd step
(S)-2-hydroxyl-1-phenylethyl carboxylamine tertiary butyl ester
Under the ice bath, (6.01g 20mmol) is dissolved in the 80mL dehydrated alcohol, and (6.05g, 16mmol), stirring at room was reacted 12 hours to add sodium borohydride with (S)-2-(tertiary butyl oxygen carbonylamino)-2-phenylacetic acid ethyl ester 22c.The reaction solution concentrating under reduced pressure, add 50mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (S)-2-hydroxyl-1-phenylethyl carboxylamine tertiary butyl ester 22d (4.75g, white liquid), productive rate: 90%.
MS?m/z(ESI)：260[M+23]
The 4th step
(S)-2-methoxyl group-1-phenylethyl carboxylamine tertiary butyl ester
Under the ice bath, (8.18g 34.5mmol) is dissolved in the 50mL tetrahydrofuran (THF) with (S)-2-hydroxyl-1-phenylethyl carboxylamine tertiary butyl ester 22d, the adding sodium hydride (2.21g, 55.2mmol), stirring reaction 30 minutes, the dropping methyl iodide (3.44mL, 55.2mmol), stirring reaction 2 hours.Adding the 10mL shrend in reaction solution goes out, with dichloromethane extraction (100mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the gained resistates system A of suitable proportion) obtains title product (S)-2-methoxyl group-1-phenylethyl carboxylamine tertiary butyl ester 22e (6.80g with the thin-layer chromatography purifying, colourless liquid), productive rate: 78%.
MS?m/z(ESI)：274[M+23]
The 5th step
(S)-2-methoxyl group-1-phenyl-ethyl amine hydrochloride
Under the ice bath, (1.60g, (V/V=1: 3) in the mixed solvent, stirring at room was reacted 12 hours 6.4mmol) to be dissolved in 20mL concentrated hydrochloric acid and tetrahydrofuran (THF) with (S)-2-methoxyl group-1-phenylethyl carboxylamine tertiary butyl ester 22e.The reaction solution concentrating under reduced pressure obtains title product (S)-2-methoxyl group-1-phenyl-ethyl amine hydrochloride 22f (1.10g, light yellow solid), productive rate: 90.0%.MS?m/z(ESI)：152[M+1]
The 6th step
(3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((S)-2-methoxyl group-1-phenylethyl carbamyl)-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester 20d (205mg, 0.35mmol) be dissolved in the 5mL triethylamine, add (S)-2-methoxyl group-1-phenyl-ethyl amine hydrochloride 22f (143mg, 1.05mmol) and 2 hydroxy pyrimidine (90mg, 1.05mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((S)-2-methoxyl group-1-phenylethyl carbamyl)-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 22g (25mg, white solid), productive rate: 10%.
MS?m/z(ESI)：740[M+1]
The 7th step
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((S)-2-methoxyl group-1-phenylethyl)-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((S)-2-methoxyl group-1-phenylethyl carbamyl)-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 22g (25mg, 0.034mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH,, merge organic phase with dichloromethane extraction (20mL * 3) greater than 7, water (10mL * 2), saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((S)-2-methoxyl group-1-phenylethyl)-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 22 (15mg, faint yellow solid), productive rate: 71.4%.
MS?m/z(ESI)：640[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.08(s，1H)，8.04(s，1H)，7.73(d，J＝7.6Hz，1H)，7.48(d，J＝7.6Hz，2H)，7.38(t，J＝7.6Hz，2H)，7.21(t，J＝7.2Hz，1H)，6.82(s，1H)，5.16(dd，J＝12.4Hz，7.2Hz，1H)，4.14(t，J＝6.4Hz，2H)，3.77(dd，J＝10.0Hz，7.6Hz，1H)，3.61(t，J＝5.6Hz，2H)，3.54(m，1H)，3.39(s，3H)，3.37(s，3H)，2.94(m，1H)，2.48(t，J＝8Hz，1H)，2.37(dd，J＝16.0Hz，4Hz，1H)，2.24(dd，J＝16.0Hz，6.8Hz，1H)，2.08(m，5H)，1.62～1.93(m，7H)，1.49(m，2H)，0.98(d，J＝6.8Hz，6H)，0.88(d，J＝6.8Hz，3H)，0.86(d，J＝6.8Hz，3H)
Embodiment 23
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-chloro-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00621
The first step
(3R, 5S, 6S, 8S)-1-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 17c (79mg, 0.14mmol) be dissolved in the 1.5mL triethylamine, in reaction solution, add 4-fluoro-benzylamine (51mg successively, 0.41mmol) and 2 hydroxy pyrimidine (39mg, 0.41mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 1-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 23a (69mg, yellow solid), productive rate: 72.0%.
MS?m/z(ESI)：730[M+23]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-chloro-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(69mg 0.10mmol) is dissolved in the 1mL methylene dichloride 1-(5-chloro-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 23a, adds 2mL concentrated hydrochloric acid and 1, the 4-dioxane (V/V=1: 1) mixing solutions, continued stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2), saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(5-chloro-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 23 (43mg, yellow solid), productive rate: 72.9%.
MS?m/z(ESI)：608[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.27(b?r.s，1H)，8.15(s，1H)，7.56(b?r.s，1H)，7.29(m，2H)，7.00(m，3H)，6.83(d，J＝8.8Hz，1H)，4.53(dd，J＝14.8Hz，6.4Hz，1H)，4.28(m，1H)，4.15(t，J＝6.0Hz，2H)，3.61(m，3H)，3.41(s，3H)，2.97(br.s，1H)，2.23～2.51(m，3H)，2.20(s，1H)，2.01～2.15(m，3H)，1.58～1.95(m，6H)，1.39～1.57(m，2H)，0.94(m，12H)
Embodiment 24
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00631
The first step
(3R, 5S, 6S, 8S)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 18c (133mg, 0.20mmol) be dissolved in the 1.5mL triethylamine, add 4-fluoro-benzylamine (75mg, 0.60mmol) and 2 hydroxy pyrimidine (57mg, 0.60mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 24a (69mg, yellow solid), productive rate: 72.0%.MS?m/z(ESI)：730[M+23]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(25mg 0.036mmol) is dissolved in the 1mL methylene dichloride 1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 24a, adds 2mL concentrated hydrochloric acid and 1, the 4-dioxane (V/V=1: 1) mixing solutions, continued stirring reaction 4 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 24 (18mg, faint yellow solid), productive rate: 86.0%.
MS?m/z(ESI)：592[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.19(br.s，1H)，8.07(dd，J＝10.4Hz，2.8Hz，1H)，7.28(dd，J＝8.4Hz，5.6Hz，2H)，7.16(br.s，1H)，6.96(t，J＝8.4Hz，2H)，6.82(dd，J＝9.2Hz，4.8Hz，1H)，6.71(m，1H)，4.48(dd，J＝14.4Hz，6.4Hz，1H)，4.28(dd，J＝14.8Hz，4.2Hz，1H)，4.11(t，J＝6.0Hz，2H)，3.60(t，J＝6.0Hz，2H)，3.48(m，1H)，3.38(s，3H)，2.79(br.s，1H)，2.45(dd，J＝16.0Hz，4.0Hz，1H)，2.17～2.36(m，2H)，2.03～2.12(m，3H)，1.51～1.92(m，6H)，1.37～1.50(m，2H)，0.90(m，12H)
Embodiment 25
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Figure G2010100039198D00641
Figure G2010100039198D00651
The first step
2-cyano-3-hydroxy-2-(hydroxymethyl) ethyl propionate
Under the ice bath, (11.30g 0.10mol) is dissolved in 100mL1, and in the 4-dioxane, (18.01g, 0.22mol), (202mg, 0.22mol), stirring at room was reacted 12 hours to drip triethylamine to add 37% formaldehyde solution with 2-ethyl cyanacetate 25a.The reaction solution concentrating under reduced pressure, with toluene extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 2-cyano-3-hydroxy-2-(hydroxymethyl) ethyl propionate 25b colourless liquid, and crude product is directly cast the step reaction.
Second step
2-cyano group-3-fluoro-2-(methyl fluoride) ethyl propionate
Under the dry ice bath, (3.46g 0.02mol) is dissolved in the 100mL methylene dichloride, and (6mL, 0.044mol), stirring at room was reacted 12 hours to drip diethylaminosulfurtrifluoride with 2-cyano-3-hydroxy-2-(hydroxymethyl) ethyl propionate 25b.Add 20mL hydrochloric acid and 20mL water, with dichloromethane extraction (100mL * 3), merge organic phase, anhydrous magnesium sulfate drying is used in water (50mL * 2), saturated common salt water washing (50mL * 2) successively, filters, filtrate decompression concentrates, obtain title product 2-cyano group-3-fluoro-2-(methyl fluoride) ethyl propionate 25c (700mg, colorless oil), productive rate: 19.8%.
The 3rd step
2-cyano group-3-fluoro-2-(methyl fluoride) propionic acid amide
With 2-cyano group-(700mg 4mmol) is dissolved in the methanol solution of 20mL 6M ammoniacal liquor 3-fluoro-2-(methyl fluoride) ethyl propionate 25c, stirring reaction 24 hours.The reaction solution concentrating under reduced pressure, (eluent: the gained resistates system B of suitable proportion) obtains title product 2-cyano group-3-fluoro-2-(methyl fluoride) propionic acid amide 25d (500mg, white solid), productive rate: 84.5% with the silica gel column chromatography purifying.
The 4th step
3-amino-2,2-two (methyl fluoride) propionic acid amide
Nitrogen atmosphere (10 normal atmosphere), (500mg 3.38mmol) is dissolved in 20mL ammoniacal liquor and the 120mL ethanol, adds the 50mg Raney Ni, stirring reaction 5 hours with 2-cyano group-3-fluoro-2-(methyl fluoride) propionic acid amide 25d.The reaction solution concentrating under reduced pressure obtains title product 3-amino-2,2-two (methyl fluoride) propionic acid amide 25e (488mg, colorless oil), productive rate: 95.0%.
The 5th step
1-methyl isophthalic acid-nitrosourea
Under the ice bath, (20.00g drips concentrated hydrochloric acid in 0.16mol) and regulates pH=3～4, and adding entry, to make the reaction gross weight be 80g to methylamine 25f, adding urea 25g (30.00g, 0.50mol), back flow reaction 3 hours, add under the room temperature Sodium Nitrite (11.13g, 0.16mol), stirring reaction 1 hour.
Under the dry ice bath, reaction solution is slowly dripped in the mixture of the ice of 60g into and the 10g vitriol oil stirring reaction 30 minutes.Filter, filtration cakes torrefaction obtains title product 1-methyl isophthalic acid-nitrosourea 25h (2.80g, yellow solid), productive rate: 16.9%.
The 6th step
Diazomethane
Under the ice bath, with 1-methyl isophthalic acid-nitrosourea 25h (2.8g, 0.027mol) be dissolved in the potassium hydroxide aqueous solution (V/V=4: 1) in the mixed solvent of 40mL ether and 50%, 50 ℃ of distillations, steam leads in the 20mL diethyl ether solution, obtain the diethyl ether solution of title product diazomethane 25i, directly cast the step reaction.
The 7th step
(S)-4-benzyl-3-(3-methyl butyl) oxazolidine-2-ketone
Under the dry ice bath, (22.80g 0.13mol) is dissolved in the 300mL tetrahydrofuran (THF) with (S)-4-benzyl oxazolidine-2-ketone 25j, the dropping n-Butyl Lithium (54mL, 0.14mol), stirring reaction 2 hours, (15.50g 0.13mol), continued stirring reaction 1 hour to drip isopropyl chloracetate.Reaction solution is added in the 50mL saturated ammonium chloride solution, concentrating under reduced pressure, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (S)-4-benzyl-3-(3-methyl butyl) oxazolidine-2-ketone 25k (33.50g, faint yellow solid) crude product is directly cast the step reaction.
The 8th step
(2S, 7S, E)-1,8-two ((S)-4-benzyl-2-oxo oxazolidine-3-yl)-2,7-di-isopropyl last of the ten Heavenly stems-4-alkene-1,8-diketone
Under the dry ice bath, with (S)-4-benzyl-3-(3-methyl butyl) oxazolidine-2-ketone 25k (28.75g, 0.11mol) be dissolved in the 60mL tetrahydrofuran (THF), drip 20mL hexamethyldisilane base amido lithium (120mL, tetrahydrofuran solution 0.12mol), stirring reaction 2 hours, drip 25mL1, (10.7g, tetrahydrofuran solution 0.050mol) continued stirring reaction 15 hours to 4-dibromo but-2-ene.In reaction solution, add the 25mL saturated ammonium chloride solution, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (2S, 7S, E)-1,8-two ((S)-4-benzyl-2-oxo oxazolidine-3-yl)-2,7-di-isopropyl last of the ten Heavenly stems-4-alkene-1,8-diketone 25m (21.10g, faint yellow solid), productive rate: 73%.
The 9th step
(S)-4-benzyl-3-((2S, 4R)-4-bromo-2-sec.-propyl-4-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyl) oxazolidine-2-ketone
Under the ice bath, with (2S, 7S, E)-1,8-two ((S)-4-benzyl-2-oxo oxazolidine-3-yl)-2,7-di-isopropyl last of the ten Heavenly stems-4-alkene-1, (2.01g 3.50mmol) is dissolved in 25mL tetrahydrofuran (THF) and water (V/V=4: 1) in the mixed solvent, add N-bromo-succinimide (642mg to 8-diketone 25m, 3.60mmol), stirring at room reaction 2 hours.In reaction solution, add 25mL water, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (S)-4-benzyl-3-((2S, 4R)-4-bromo-2-sec.-propyl-4-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyl) oxazolidine-2-ketone 25n (1.40g, white solid), productive rate: 80.9%.
MS?m/z(ESI)：494[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.40～7.27(m，5H)，4.71(m，1H)，4.54(m，1H)，4.12～4.22(m，3H)，4.01(m，1H)，3.50(dd，J＝13.2Hz，3.2Hz，1H)，2.70(m，2H)，2.52(m，1H)，2.14～2.36(m，4H)，2.01(m，1H)，1.08～0.95(m，12H)
The tenth step (S)-3-((2S, 4S)-4-nitrine-2-sec.-propyl-4-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyl)-4-benzyl oxazolidine-2-ketone
With (S)-4-benzyl-3-((2S, 4R)-4-bromo-2-sec.-propyl-4-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyl) (1.35g 3.70mmol) is dissolved in 12mLN to oxazolidine-2-ketone 25n, in the dinethylformamide, add 1.2mL 1,3-dimethyl-3,4,5,6-tetrahydrochysene-2-pyrimidone and sodiumazide (355mg, 5.46mmol), 40 ℃ of following stirring reactions 24 hours.In reaction solution, add 10mL water, with ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (S)-3-((2S, 4S)-4-nitrine-2-sec.-propyl-4-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyl)-4-benzyl oxazolidine-2-ketone 25o (788mg, light yellow viscous liquid), productive rate: 63.0%.
MS?m/z(ESI)：457[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ7.40～7.25(m，5H)，4.75(m，1H)，4.49(dd，J＝13.2Hz，6.0Hz，1H)，4.12～4.28(m，3H)，4.08(m，1H)，3.36(dd，J＝13.2Hz，3.6Hz，1H)，3.17(m，1H)，2.79(dd，J＝13.2Hz，10.0Hz，1H)，2.69(m，1H)，1.93～2.36(m，4H)，1.82(m，1H)，1.13～0.88(m，12H)
The 11 step
(2S, 4S)-4-nitrine-2-sec.-propyl-4-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyric acid
Under the ice bath, with (S)-3-((2S, 4S)-4-nitrine-2-sec.-propyl-4-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyl)-4-benzyl oxazolidine-2-ketone 25o (780mg, 1.70mmol) be dissolved in the mixing solutions of 40mL tetrahydrofuran (THF) and 10mL water, add hydrogen peroxide (348mg, 10.20mmol) and lithium hydroxide (143mg, 3.40mmol), stirring at room reaction 12 hours.The sodium sulfite solution and the 10mL saturated sodium bicarbonate solution that in reaction solution, add 15mL1.5M, with dichloromethane extraction (100mL * 3), water is regulated pH with hydrochloric acid and is approximated 1, with dichloromethane extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (2S, 4S)-4-nitrine-2-sec.-propyl-4-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyric acid 25p (434mg, colourless viscous liquid), productive rate: 85.6%.
MS?m/z(ESI)：297[M+1]
The 12 step
(3R, 5S)-5-nitrine-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyric acid
Will (2S, 4S)-4-nitrine-2-sec.-propyl-4-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyric acid 25p (108mg, 0.36mmol) be dissolved in 1mL thionyl chloride and 1 pyridine, 40 ℃ of following stirring reactions 2 hours, concentrating under reduced pressure, vacuum-drying 1 hour.
Under the ice bath, the gained resistates is dissolved in the 15mL tetrahydrofuran (THF), drips and advance to make by oneself 8mL diazomethane 25i, stirring reaction 2 hours, room temperature continued stirring reaction 12 hours.Reaction solution concentrating under reduced pressure, resistates directly drop into the next step.
With silver suboxide (120mg, 0.50mmol), yellow soda ash (290mg, 2.70mmol) and Sulfothiorine (301mg 1.23mmol) is dissolved in the 2mL water, drip 2mL and go up step reaction gained resistates (117mg, 0.36mmol) 1,4-dioxane solution, 70 ℃ of following stirring reactions 2 hours, filter, with dichloromethane extraction (30mL * 3), water is regulated pH with concentrated hydrochloric acid and is approximated 1, with dichloromethane extraction water (30mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, filters, filtrate decompression concentrates, obtain title product (3R, 5S)-5-nitrine-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyric acid 25q (93mg, brown viscous liquid), productive rate: 82.0%.
The 13 step
(3R, 5S)-5-nitrine-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-N-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) valeramide
With (3R, 5S)-5-nitrine-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl) butyric acid 25q (112mg, 0.36mmol) be dissolved in the 15mL acetonitrile, add diisopropylethylamine (0.18mL, 0.36mmol) and benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (136mg, 0.36mmol), stirring reaction 10 minutes adds 6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-acid amides 20c (79mg, 0.36mmol), continued stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S)-5-nitrine-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-N-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) valeramide 25r (84mg, white solid), productive rate: 50.0%.
MS?m/z(ESI)：515[M+1]
The 14 step
(2S, 4S, 5S, 7R)-and 5-nitrine-4-hydroxyl-2,7-di-isopropyl-9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-oxo n-nonanoic acid
With (3R, 5S)-5-nitrine-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-N-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) valeramide 25r (84mg, 0.16mmol) be dissolved in 1mL 1, in the 4-dioxane, add 1mL water and lithium hydroxide (8mg, 0.18mmol), stirring at room reaction 6 hours.The buffered soln cancellation reaction that in reaction solution, adds the pH=7 that is made into by sodium hydrogen phosphate and SODIUM PHOSPHATE, MONOBASIC, with ethyl acetate extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product (2S, 4S, 5S, 7R)-5-nitrine-4-hydroxyl-2,7-di-isopropyl-9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-oxo n-nonanoic acid 25s (93mg, yellow solid) crude product.
MS?m/z(ESI)：533[M+1]
The 15 step
(2S, 4S, 5S, 7R)-and 5-nitrine-4-(tertiary butyl dimethyl Si base)-2,7-di-isopropyl-9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-oxo n-nonanoic acid
With (2S, 4S, 5S, 7R)-5-nitrine-4-hydroxyl-2,7-di-isopropyl-9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-(92mg 0.17mmol) is dissolved in 5mLN, in the dinethylformamide to 9-oxo n-nonanoic acid 25s, add dimethyl tertiary butyl chloride silane (130mg, 0.86mmol) and imidazoles (94mg, 1.38mmol), stirring reaction 12 hours.In reaction solution, add the 10mL shrend reaction of going out, with ethyl acetate extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-nitrine-4-(tertiary butyl dimethyl Si base)-2,7-di-isopropyl-9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-oxo n-nonanoic acid 25t (48mg, colorless solid), productive rate: 43.0%.
MS?m/z(ESI)：647[M+1]
The 16 step
(2S, 4S, 5S, 7R)-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-5-nitrine-4-(tertiary butyl dimethyl Si base)-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
With (2S, 4S, 5S, 7R)-and 5-nitrine-4-(tertiary butyl dimethyl Si base)-2,7-di-isopropyl-9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-oxo n-nonanoic acid 25t (46mg, 0.070mmol) be dissolved in the 10mL acetonitrile, add diisopropylethylamine (0.1mL, 0.070mmol) and benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (27mg, 0.070mmol), stirring reaction 10 minutes, add 3-amino-2, (12mg 0.78mmol), continued stirring reaction 12 hours to 2-two (methyl fluoride) propionic acid amide 25e.The reaction solution concentrating under reduced pressure, with the silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-5-nitrine-4-(tertiary butyl dimethyl Si base)-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 25u (30mg, colourless viscous liquid), productive rate: 54.0%.
MS?m/z(ESI)：781[M+1]
The 17 step
(2S, 4S, 5S, 7R)-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-5-nitrine-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Will (2S, 4S, 5S, 7R)-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-5-nitrine-4-(tertiary butyl dimethyl Si base)-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 25u (30mg 0.043mmol) is dissolved in the 1.5mL tetrahydrofuran (THF), and the adding tetrabutyl ammonium fluoride (34mg, 0.10mmol), stirring reaction 12 hours.In reaction solution, add the 5mL shrend reaction of going out, with ethyl acetate extraction (20mL * 3), merge organic phase, water (5mL * 2) and saturated common salt water washing (5mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-5-nitrine-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 25v (14mg, faint yellow solid), productive rate: 55.0%.
The 18 step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Will (2S, 4S, 5S, 7R)-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-5-nitrine-4-hydroxyl-2,7-di-isopropyl-N 9(14mg 0.021mmol) is dissolved in the 5mL ethyl acetate-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 25v, adds palladium/carbon (3mg, 10%), hydrogen exchange three times, stirring reaction 12 hours.Filter, filtrate decompression concentrates, with the thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-difluoromethyl-3-oxopropyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 25 (7mg, colorless solid), productive rate: 54.0%.
MS?m/z(ESI)：641[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.13(s，1H)，8.05(s，1H)，7.50(s，1H)，6.84(s，1H)，7.00(s，1H)，6.84(s，1H)，4.80～4.62(m，6H)，4.15(t，J＝6.4Hz，2H)，4.05(m，1H)，3.80(m，1H)，3.62(t，J＝5.6Hz，2H)，3.41(s，3H)，3.00～1.50(m，18H)，0.98～0.90(m，12H)
Embodiment 26
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-3,3-dimethyl-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Figure G2010100039198D00711
The first step
5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes
With 2, (7.38g 0.055mol) is dissolved in the 15mL tetrahydrofuran (THF) 3-dihydro-1H-5-indanol 10a, add 3-methoxyl group-1-propyl alcohol 1a (5.65g, 0.063mol) and triphenylphosphine (17g, 0.065mol), the adding diethyl azodiformate (5.65g, 0.063mol), stirring reaction 3 hours.With the reaction solution concentrating under reduced pressure, (eluent: the gained resistates system B of suitable proportion) obtains title product 5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes 26a (7.88g, yellow solid), productive rate: 69.5% with the silica gel column chromatography purifying.
Second step
5-(3-methoxy propoxy)-2,3-dihydro-1H-1-Indanone
With 5-(3-methoxy propoxy)-2,3-dihydro-1H-indenes 26a (7.88g 0.038mol) is dissolved in the 205mL acetate, and adding chromic oxide (11.40g, 0.11mol), stirring reaction 4 hours.In reaction solution, add the 10mL shrend reaction of going out, with dichloromethane extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated common salt water washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product 5-(3-methoxy propoxy)-2,3-dihydro-1H-1-Indanone 26b (4.50g, yellow solid), productive rate: 54.0%.
The 3rd step
5-(3-methoxy propoxy)-1,1-dimethyl-2,3-dihydro-1H-indenes
Under the dry ice bath, (15.52mL 0.050mol) is dissolved in the 30mL methylene dichloride, adds 2 with titanium tetrachloride, 4-zinc methide (7.16g, 0.075mol), stirring reaction 30 minutes drips 10mL5-(3-methoxy propoxy)-2,3-dihydro-1H-1-Indanone 26b (5.54g, 0.025mol) dichloromethane solution, continued stirring reaction 30 minutes, stirring at room reaction 2 hours.In reaction solution, add 5mL methyl alcohol cancellation reaction, the reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 5-(3-methoxy propoxy)-1,1-dimethyl-2,3-dihydro-1H-indenes 26c (4.22g, light yellow oil), productive rate: 72.0%.
The 4th step
5-(3-methoxy propoxy)-1,1-dimethyl-6-nitro-2,3-dihydro-1H-indenes
With 5-(3-methoxy propoxy)-1,1-dimethyl-2,3-dihydro-1H-indenes 26c (1.01g 4.20mmol) is dissolved in the 10mL acetate, drip concentrated nitric acid (269mg, 4.20mmol), 60 ℃ of following stirring reactions 2 hours.Reaction solution washes (100mL * 4) with water, and ethyl acetate extraction (100mL * 3) merges organic phase, and water (50 successively
ML * 2) and saturated common salt water washing (50mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 5-(3-methoxy propoxy)-1 with the silica gel column chromatography purifying, 1-dimethyl-6-nitro-2,3-dihydro-1H-indenes 26d (534mg, yellow oil), productive rate: 45.6%.
MS?m/z(ESI)：280[M+1]
The 5th step
6-(3-methoxy propoxy)-3,3-dimethyl-2,3-dihydro-1H-indenes-5-acid amides
With 5-(3-methoxy propoxy)-1,1-dimethyl-6-nitro-2, (630mg 0.010mmol) is dissolved in the 10mL tetrahydrofuran (THF) 3-dihydro-1H-indenes 26d, adds palladium/carbon (60mg, 10%), hydrogen exchange three times, stirring reaction 12 hours.Filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 6-(3-methoxy propoxy)-3,3-dimethyl-2,3-dihydro-1H-indenes-5-acid amides 26e (372mg, yellow oily), productive rate: 66.0%.
The 6th step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(3-dihydro-1H-indenes-5-base is amino for 6-(3-methoxy propoxy)-3,3-dimethyl-2)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (616mg, 1.60mmol) be dissolved in the 20mL acetonitrile, add diisopropylethylamine (1.2mL, 1.60mmol) and benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (606mg, 1.60mmol), stirring reaction 10 minutes adds 6-(3-methoxy propoxy)-3,3-dimethyl-2, (350mg 1.40mmol), continued stirring reaction 12 hours to 3-dihydro-1H-indenes-5-acid amides 26e.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(3-dihydro-1H-indenes-5-base is amino for 6-(3-methoxy propoxy)-3,3-dimethyl-2)-5-oxo amyl group carboxylamine tertiary butyl ester 26f (622mg, yellow oil), productive rate 72.0%.
MS?m/z(ESI)：617[M+1]
The 7th step
(3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(3-dihydro-1H-indenes-5-base is amino for 6-(3-methoxy propoxy)-3,3-dimethyl-2)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(6-(3-methoxy propoxy)-3,3-dimethyl-2,3-dihydro-1H-indenes-5-base is amino)-(250mg 0.40mmol) is dissolved in the 5mL triethylamine 5-oxo amyl group carboxylamine tertiary butyl ester 26f, add 4-fluoro-benzylamine (152mg, 1.20mmol) and 2 hydroxy pyrimidine (116mg, 1.20mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-3,3-dimethyl-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 26g (171mg, yellow oil), productive rate: 58.0%.
MS?m/z(ESI)：742[M+1]
The 8th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-3,3-dimethyl-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(4-luorobenzyl carbamyl)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-3,3-dimethyl-2,3-dihydro-1H-indenes-5-base is amino)-(171mg 0.23mmol) is dissolved in the 1mL methylene dichloride 9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 26g, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 4 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (30mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(4-luorobenzyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-3,3-dimethyl-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 26 (115mg, white solid), productive rate: 78.0%.
MS?m/z(ESI)：642[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.13(s，1H)，7.99(s，1H)，7.61(t，J＝6.0Hz，1H)，7.33(dd，J＝8.0Hz，5.6Hz，2H)，7.00(t，J＝8.8Hz，2H)，6.80(s，1H)，4.55(dd，J＝14.8Hz，6.8Hz，1H)，4.29(dd，J＝14.8Hz，5.2Hz，1H)，4.15(t，J＝6.0Hz，2H)，3.74(t，J＝8.8Hz，1H)，3.61(t，J＝6.0Hz，2H)，3.52(s，1H)，3.40(s，3H)，2.98(m，1H)，2.86(t，J＝7.2Hz，2H)，2.51(dd，J＝16.4Hz，2.8Hz，1H)，2.43(t，J＝10Hz，1H)，2.26(dd，J＝16.4Hz，6.8Hz，1H)，2.11(m，3H)，1.71～2.05(m，6H)，1.42～1.70(m，2H)，1.26(m，2H)，1.25(s，6H)，0.90(m，12H)
Embodiment 27
(2S, 4S, 5S, 7R)-5-amino-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N 1-((S)-1-methoxyl group-3-phenyl propyl-2-yl) azelaoyl amine
Figure G2010100039198D00731
Figure G2010100039198D00741
The first step
(S)-2-(dibenzyl amino)-3-phenylpropionic acid benzyl ester
With (S)-2-amino-3-phenylpropionic acid 27a (1.65g, 0.010mol), salt of wormwood (2.76g, 0.020mol) and sodium hydroxide (0.80g 0.020mol) is dissolved in the 20mL water, dripping bromine methylbenzene (4.11mL, 0.035mol), 60 ℃ of following stirring reactions 6 hours.With dichloromethane extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (S)-2-(dibenzyl amino)-3-phenylpropionic acid benzyl ester 27b (4.6g, colourless liquid) crude product.MS?m/z(ESI)：436[M+1]
Second step
(S)-2-(dibenzyl amino)-3-phenyl-1-propyl alcohol
Under the ice bath, (4.35g 0.010mol) is dissolved in the 25mL tetrahydrofuran (THF), and add lithium aluminum hydride (0.95g, 0.025mol), stirring at room was reacted 12 hours in batches with (S)-2-(dibenzyl amino)-3-phenylpropionic acid benzyl ester 27b.The sodium hydroxide solution that in reaction solution, adds 20mL 10%, filter, with ethyl acetate extraction (50mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, filter, filtrate decompression concentrates, and obtains title product (S)-2-(dibenzyl amino)-3-phenyl-1-propyl alcohol 27c (3.60g, light yellow oil) crude product.
MS?m/z(ESI)：332[M+1]
The 3rd step
(S)-and N, N-dibenzyl-1-methoxyl group-3-phenyl propyl-2-acid amides
Under the ice bath, with (S)-2-(dibenzyl amino)-3-phenyl-1-propyl alcohol 27c (3.60g, 0.01mol) be dissolved in the 25mL tetrahydrofuran (THF), add sodium hydride (0.60g in batches, 0.015mol), stirring at room reaction 3 hours drips methyl iodide (0.94mL, 0.015mol), continued stirring reaction 12 hours.Adding the 20mL shrend in reaction solution goes out, with dichloromethane extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (S)-N, N-benzyl-1-methoxyl group-3-phenyl propyl-2-acid amides 27d (3.01g, light yellow liquid), productive rate: 87%.
MS?m/z(ESI)：346[M+1]
The 4th step
(S)-1-methoxyl group-3-phenyl propyl-2-acid amides
With (S)-N, (3.01g 8.70mmol) is dissolved in the 25mL tetrahydrofuran (THF) N-dibenzyl-1-methoxyl group-3-phenyl propyl-2-acid amides 27d, adds the 1.2g palladium hydroxide in batches, hydrogen exchange three times, 45 ℃ of following stirring reactions 12 hours.Filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product (S)-1-methoxyl group-3-phenyl propyl-2-acid amides 27e (1.10g, light yellow liquid), productive rate: 76.0% with the silica gel column chromatography purifying.
MS?m/z(ESI)：166[M+1]
The 5th step
(3R, 5S, 6S, 8S)-1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-8-((S)-1-methoxyl group-3-phenyl propyl-2-base carbamyl)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid uncle fourth
The base ester
With (1S, 3R)-5-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 11c (183mg, 0.30mmol) be dissolved in the 2mL triethylamine, add (S)-1-methoxyl group-3-phenyl propyl-2-acid amides 27e (149mg, 0.90mmol) and 2 hydroxy pyrimidine (86mg, 0.90mmol), 85 ℃ of following stirring reactions 18 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-8-((S)-1-methoxyl group-3-phenyl propyl-2-base carbamyl)-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 27f (30mg, faint yellow solid), productive rate: 13.0%.
MS?m/z(ESI)：770[M+1]
The 6th step
(2S, 4S, 5S, 7R)-5-amino-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N 1-((S)-1-methoxyl group-3-phenyl propyl-2-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-((S)-1-methoxyl group-3-phenyl propyl-2-base carbamyl)-(30mg 0.039mmol) is dissolved in the 1mL methylene dichloride 9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 27f 1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-8-, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N 1-((S)-1-methoxyl group-3-phenyl propyl-2-yl) azelaoyl amine 27 (20mg, faint yellow solid), productive rate: 80.0%.
MS?m/z(ESI)：670[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.31(d，J＝2Hz，1H)，8.12(s，1H)，7.29(m，4H)，7.21(m，1H)，7.08(m，2H)，6.75(s，1H)，4.24～4.49(m，2H)，4.16(m，2H)，3.60(t，J＝6.0Hz，2H)，3.42(s，3H)，3.38(s，3H)，3.40(m，1H)，2.78～3.07(m，4H)，2.23～2.53(m，3H)，2.05～2.25(m，5H)，1.55～1.95(m，6H)，1.31(s，9H)，0.94(m，12H)
Embodiment 28
(2S, 4S, 5S, 7R)-and 5-amino-N9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N1-(3, the 4-difluorobenzyl) azelaoyl amine
Figure G2010100039198D00761
The first step
2,4, the 5-benzamide trifluoroacetate
With 2,4, (1.76g 0.010mol) is dissolved in the 10mL methylene dichloride 5-trifluoro-benzoic acid 28a, add 2 N, and dinethylformamide and oxalyl chloride (1.52g, 0.012mol), stirring reaction 1.5 hours, the reaction solution concentrating under reduced pressure is added drop-wise in the 50mL ammoniacal liquor, continues stirring reaction 30 minutes.Filter, filtration cakes torrefaction obtains title product 2,4,5-benzamide trifluoroacetate 28b (3.13g, white solid) crude product.
Second step
(3, the 4-difluorophenyl) methylamine
Under the ice bath, with 2,4, (3.13g 0.018mol) is dissolved in the 20mL tetrahydrofuran (THF) 5-benzamide trifluoroacetate 28b, and (1.35g, 0.025mol), stirring at room was reacted 12 hours to add lithium aluminum hydride.In reaction solution, add the sodium hydroxide solution of 7mL 15%, filter, with ethyl acetate extraction (50mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (20mL * 2) and saturated common salt water washing (20mL * 2) successively, filters, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product (3, the 4-difluorophenyl) methylamine 28c (1.40g with the silica gel column chromatography purifying, yellow oil), productive rate: 87.5%.
The 3rd step
(3R, 5S, 6S, 8S)-1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo-8-(3,4-difluorobenzyl carbamyl) decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 11c (183mg, 0.30mmol) be dissolved in the 2mL triethylamine, add (3, the 4-difluorophenyl) methylamine 28c (145mg, 0.90mmol) and 2 hydroxy pyrimidine (86mg, 0.90mmol), 80 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo-8-(3,4-difluorobenzyl carbamyl) decane-5-aminocarbamic acid tertiary butyl ester 28d (55mg, faint yellow solid), productive rate: 13.0%.
MS?m/z(ESI)：766[M+1]
The 4th step
(2S, 4S, 5S, 7R)-5-amino-N 9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N 1-(3, the 4-difluorobenzyl) azelaoyl amine)
Under the ice bath, with (3R, 5S, 6S, 8S)-1-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo-8-(3,4-difluorobenzyl carbamyl) decane-5-aminocarbamic acid tertiary butyl ester 28d (65mg, 0.087mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1, and 4-dioxane mixing solutions (V/V=1: 1), stirring reaction 5 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N9-(the 5-tertiary butyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N1-(3, the 4-difluorobenzyl) azelaoyl amine 28 (41mg, white solid), productive rate: 73.0%.
MS?m/z(ESI)：648[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.28(d，J＝2.4Hz，1H)，8.07(s，1H)，7.79(t，J＝6.0Hz，1H)，7.08(m，4H)，6.82(d，J＝8.8Hz，1H)，4.54(dd，J＝14.8Hz，6.8Hz，1H)，4.17(dd，J＝14.8Hz，4.8Hz，1H)，4.12(t，J＝6.0Hz，2H)，3.69(t，J＝8.8Hz，1H)，3.57(t，J＝6.0Hz，2H)，3.36(s，3H)，2.98(m，1H)，2.39～2.50(m，2H)，2.28(dd，J＝16.0Hz，8.0Hz，1H)，2.07(m，3H)，1.69～2.05(m，4H)，1.35～1.69(m，2H)，1.26(m，2H)，1.25(s，9H)，0.90(m，12H)
Embodiment 29
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00781
The first step
(3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid uncle fourth
The base ester
With (1S, 3R)-5-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 6g (160mg, 0.26mmol) be dissolved in the 1mL triethylamine, add 3-amino-2, and 2-dimethyl-propionic acid amide 1g (90mg, 0.77mmol) and 2 hydroxy pyrimidine (74mg, 0.77mmol), 80 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 29a (95mg, yellow solid), productive rate: 50.0%.
MS?m/z(ESI)：769[M+23]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3-amino-2,2-dimethyl-3-oxopropyl carbamyl)-1-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 29a (95mg, 0.13mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3-amino-2,2-dimethyl-3-oxopropyl)-N 9-(5-(cyclopentyl-methyl)-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 29 (22mg, faint yellow solid), productive rate: 26.9%.
MS?m/z(ESI)：647[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.08(s，1H)，8.05(s，1H)，7.18(br.s，1H)，6.90(b?r.s，1H)，6.80(m，3H)，4.10(t，J＝6.0Hz，2H)，3.64(dd，J＝13.2Hz，7.2Hz，1H)，3.57(m，3H)，3.36(s，3H)，3.13(dd，J＝13.6Hz，4.4Hz，1H)，2.87(m，1H)，2.52(d，J＝8Hz，2H)，2.23～2.46(m，3H)，1.94～2.19(m，4H)，1.41～1.92(m，13H)，1.20(s，6H)，1.14(m，3H)，0.90(m，12H)
Embodiment 30
(2S, 4S, 5S, 7R)-5-amino-N 1-(3,5-two (trifluoromethyl) benzyl)-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
The first step
(3R, 5S, 6S, 8S)-8-(3,5-two (trifluoromethyl) benzylamino formyl)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 18c (188mg, 0.33mmol) be dissolved in the 2mL triethylamine, add (3,5-two (trifluoromethyl) phenyl) methylamine (242mg, 0.99mmol) and 2 hydroxy pyrimidine (95mg, 0.99mmol), 80 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-(3,5-two (trifluoromethyl) benzylamino formyl)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 30a (90mg, faint yellow solid), productive rate: 33.5%.
MS?m/z(ESI)：832[M+23]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(3,5-two (trifluoromethyl) benzyl)-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-8-(3,5-two (trifluoromethyl) benzylamino formyl)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 30a (90mg, 0.11mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(3,5-two (trifluoromethyl) benzyl)-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 30 (60mg, faint yellow solid), productive rate: 76.1%.MS?m/z(ESI)：710[M+1]
1H?NMR(400MHz，CDCl 3，pm)：δ8.20(s，1H)，8.03(m，1H)，7.77(br.s，2H)，7.69(br.s，2H)，6.80(m，1H)，6.68(m，1H)，4.74(dd，J＝16.0Hz，6.4Hz，1H)，4.35(dd，J＝16.0Hz，5.2Hz，1H)，4.10(t，J＝6.0Hz，2H)，3.60(t，J＝6.0Hz，2H)，3.50(t，J＝8.4Hz，1H)，3.38(s，3H)，2.85(m，1H)，2.23～2.53(m，3H)，2.0～2.19(m，3H)，1.55～1.95(m，5H)，1.46(t，J＝12Hz，1H)，1.13～1.40(m，2H)，0.90(m，12H)
Embodiment 31
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-N 1-(4-fluoro-5-(trifluoromethyl) benzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00801
The first step
(3R, 5S, 6S, 8S)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(4-fluoro-5-(trifluoromethyl) benzylamino formyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 18c (188mg, 0.33mmol) be dissolved in the 2mL triethylamine, add (4-fluoro-5-(trifluoromethyl) phenyl) methylamine (192mg, 0.99mmol) and 2 hydroxy pyrimidine (95mg, 0.99mmol), 80 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(4-fluoro-5-(trifluoromethyl) benzylamino formyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 31a (24mg, faint yellow solid), productive rate: 9.5%.
MS?m/z(ESI)：782[M+23]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-N 1-(4-fluoro-5-(trifluoromethyl) benzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(24mg 0.030mmol) is dissolved in the 1mL methylene dichloride 1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(4-fluoro-5-(trifluoromethyl) benzylamino formyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 31a, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system A of suitable proportion) obtains title product (2S with the thin-layer chromatography purifying, 4S, 5S, 7R)-5-amino-N9-(5-fluoro-2-(3-methoxy propoxy) phenyl)-N1-(4-fluoro-5-(trifluoromethyl) benzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 31 (16mg, faint yellow solid), productive rate: 80.0%.
MS?m/z(ESI)：660[M+1]
Embodiment 32
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-fluorine o-2-(3-methoxy propyl methyl) phenyl)-N 1-(3-fluoro-4-(trifluoromethyl) benzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
The first step
(3R, 5S, 6S, 8S)-1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(3-fluoro-4-(trifluoromethyl) benzylamino formyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 18c (188mg, 0.33mmol) be dissolved in the 2mL triethylamine, add (3-fluoro-4-(trifluoromethyl) phenyl) methylamine (192mg, 0.99mmol) and 2 hydroxy pyrimidine (95mg, 0.99mmol), 80 ℃ of following stirring reactions 18 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(3-fluoro-4-(trifluoromethyl) benzylamino formyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 32a (24mg, yellow solid), productive rate: 9.5%.
MS?m/z(ESI)：760[M+1]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-fluorine o-2-(3-methoxy propyl methyl) phenyl)-N 1-(3-fluoro-4-(trifluoromethyl) benzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(24mg 0.030mmol) is dissolved in the 1mL methylene dichloride 1-(5-fluoro-2-(3-methoxy propoxy) phenyl amino)-8-(3-fluoro-4-(trifluoromethyl) benzylamino formyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 32a, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(5-fluorine o-2-(3-methoxy propyl methyl) phenyl)-N 1-(3-fluoro-4-(trifluoromethyl) benzyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 32 (16mg, faint yellow solid), productive rate: 80.0%.
MS?m/z(ESI)：660[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.13(d，J＝10.4，1H)，8.09(s，1H)，7.51(m，1H)，7.1(m，3H)，6.81(m，1H)，6.69(m，1H)，4.50(m，2H)，4.10(t，J＝6.4Hz，2H)，3.65(m，1H)，3.60(t，J＝6.4Hz，2H)，3.57(s，3H)，3.20(m，1H)，2.50～1.20(m，12H)，0.97～0.85(m，12H)
Embodiment 33
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl)-N 1-(2,4, the 5-trifluoro-benzyl) azelaoyl amine
Figure G2010100039198D00821
The first step
(3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo-8-(2,4,5-trifluoro-benzyl carbamyl) decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-(158mg 0.26mmol) is dissolved in the 5mL triethylamine 5-oxo amyl group carboxylamine tertiary butyl ester 20d 5-, add (2,4,5-trifluorophenyl) methylamine 28c (129mg, 0.80mmol) and 2 hydroxy pyrimidine (76mg, 0.80mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo-8-(2,4,5-trifluoro-benzyl carbamyl) decane-5-aminocarbamic acid tertiary butyl ester 33a (55mg, faint yellow solid), productive rate: 13.0%.
MS?m/z(ESI)：766[M+1]
Second step
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl)-N 1-(2,4, the 5-trifluoro-benzyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo-8-(2,4,5-trifluoro-benzyl carbamyl) decane-5-aminocarbamic acid tertiary butyl ester 33a (40mg, 0.050mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH,, merge organic phase with dichloromethane extraction (20mL * 3) greater than 7, water (10mL * 2) and saturated common salt water washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl)-N 1-(2,4, the 5-trifluoro-benzyl) azelaoyl amine 33 (23mg, yellow solid), productive rate: 68.0%.MS?m/z(ESI)：650[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.11(s，1H)，7.99(s，1H)，7.92(t，J＝6.0Hz，1H)，7.26(m，1H)，6.83(m，2H)，4.55(dd，J＝15.2Hz，6.4Hz，1H)，4.24(dd，J＝15.2Hz，4.8Hz，1H)，4.13(t，J＝6.0Hz，2H)，3.61(m，3H)，3.40(s，3H)，3.05(m，1H)，2.83(m，4H)，2.28～2.51(m，3H)，1.98～2.14(m，5H)，1.75～1.97(m，4H)，1.69(t，J＝11.2Hz，1H)，1.50(m，1H)，1.31(m，2H)，0.88～0.95(m，12H)
Embodiment 34
(2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) azelaoyl amine
Figure G2010100039198D00831
The first step
(3R, 5S, 6S, 8S)-8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 1k (42mg, 0.077mmol) be dissolved in the 1mL triethylamine, add 2-furylamine (22mg, 0.23mmol) and 2 hydroxy pyrimidine (22mg, 0.23mmol), 80 ℃ of following stirring reactions 24 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 34a (32mg, faint yellow semisolid), productive rate: 65.3%.
MS?m/z(ESI)：646[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.28(d，J＝7.6Hz，1H)，8.01(b?r.s，1H)，7.33(b?r.s，1H)，7.05(t，J＝7.2Hz，1H)，6.95(m，2H)，6.26(m，3H)，5.02(br.d，J＝8.8Hz，1H)，4.3～4.6(m，2H)，4.18(t，J＝6.4Hz，2H)，3.73(b?r.d，J＝10.0Hz，1H)，3.62(t，J＝6.0Hz，2H)，3.46(m，1H)，3.37(s，3H)，2.42(dd，J＝15.6Hz，4.8Hz，1H)，2.31(dd，J＝15.6Hz，8Hz，1H)，2.10～2.25(m，3H)，1.6～2.0(m，6H)，1.44(s，9H)，1.37(m，1H)，0.95(m，12H)
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(32mg 0.049mmol) is dissolved in the 1mL methylene dichloride 8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 34a, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, successively water (5mL * 2) and saturated sodium-chloride washing (5mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy) phenyl) azelaoyl amine 34 (18mg, faint yellow solid), productive rate: 66.7%.
MS?m/z(ESI)：546[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.23(dd，J＝8Hz，1.2Hz，1H)，8.14(b?r.s，1H)，7.40(m，2H)，7.07(dt，J＝8.0Hz，1.6Hz，1H)，6.95(m，2H)，6.26(m，2H)，4.54(dd，J＝15.6Hz，6Hz，1H)，4.35(dd，J＝15.6Hz，4.8Hz，1H)，4.18(t，J＝6.4Hz，2H)，3.63(m，3H)，3.42(s，3H)，2.96(m，1H)，2.49(dd，J＝16.4Hz，3.2Hz，1H)，2.25～2.45(m，2H)，2.05～2.2(m，3H)，1.75～2.0(m，4H)，1.67(t，J＝11.2Hz，1H)，1.4～1.55(m，2H)，0.94(m，12H)
Embodiment 35
(2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine
Figure G2010100039198D00841
The first step
(3R, 5S, 6S, 8S)-8-((furans-2-ylmethyl) carboxylamine)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 12c (75mg, 0.13mmol) be dissolved in the 2mL triethylamine, add 2-furylamine (39mg, 0.40mmol) and 2 hydroxy pyrimidine (38mg, 0.40mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-((furans-2-ylmethyl) carboxylamine)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 35a (65mg, yellow semi-solid), productive rate: 73.8%.
MS?m/z(ESI)：660[M+1]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(65mg 0.10mmol) is dissolved in the 1mL methylene dichloride 8-((furans-2-ylmethyl) carboxylamine)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-5-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 35a, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, successively water (5mL * 2) and saturated sodium-chloride washing (5mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-5-aminomethyl phenyl) azelaoyl amine 35 (30mg, off-white color solid), productive rate: 54.5%.
MS?m/z(ESI)：560[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.13(br.s，1H)，8.07(br.s，1H)，7.55(br.s，1H)，7.41(s，1H)，6.83(m，2H)，6.26(m，2H)，4.55(dd，J＝16Hz，6.0Hz，1H)，4.39(dd，J＝16Hz，4.4Hz，1H)，4.15(t，J＝6.0Hz，2H)，3.71(br.s，1H)，3.63(t，J＝6.0Hz，2H)，3.41(s，3H)，3.01(br.s，1H)，2.52(br.d，J＝14.4Hz，1H)，2.43(t，J＝9.6Hz，1H)，2.31(m，1H)，2.30(s，3H)，2.05～2.19(m，3H)，1.76～2.04(m，4H)，1.39～1.75(m，4H)，0.95(m，12H)
Embodiment 36
(2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-4-aminomethyl phenyl) azelaoyl amine
Figure G2010100039198D00851
Figure G2010100039198D00861
The first step
2-(3-methoxy propoxy)-4-methyl isophthalic acid-oil of mirbane
With 5-methyl-2-nitrophenols (1.01g 6.53mmol) is dissolved in the 10mL acetonitrile, add 3-methoxy-propyl methanesulfonates 10g (0.65g, 7.18mmol) and Anhydrous potassium carbonate (2.70g, 19.59mmol), 70 ℃ of following stirring reactions 12 hours.Filter, add the 150mL ethyl acetate, use saturated sodium bicarbonate (50mL * 2), saturated ammonium chloride (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 2-(3-methoxy propoxy)-4-methyl isophthalic acid-oil of mirbane 36a (615mg, orange red spicule) crude product, productive rate: 42.0%.
Second step
2-(3-methoxy propoxy)-4-monomethylaniline
With 2-(3-methoxy propoxy)-4-methyl isophthalic acid-oil of mirbane 36a (615mg 2.73mmol) is dissolved in the 10mL acetonitrile, add iron powder (1.22g, 21.84mmol), dropwise add acetate (2.46g, 40.95mmol), stirring reaction 5 hours.Filter, regulate pH greater than 10, in filtrate, add the 50mL ethyl acetate, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product 2-(3-methoxy propoxy)-4-monomethylaniline 36b (100mg, yellow oil), productive rate: 17.8%.
The 3rd step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-4-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester
Will (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (116mg, 0.30mmol) be dissolved in the 5mL acetonitrile, add diisopropylethylamine (0.15mL, 0.30mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (114mg, 0.30mmol), stirring reaction 10 minutes, (59mg 0.30mmol), continues to stir 12 hours to add 2-(3-methoxy propoxy)-4-monomethylaniline 36b.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-4-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 36c (75mg, yellow semi-solid), productive rate: 44.4%.
MS?m/z(ESI)：563[M+1]
The 4th step
(3R, 5S, 6S, 8S)-8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-4-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(3-methoxy propoxy)-4-aminomethyl phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 36c (85mg, 0.15mmol) be dissolved in the 2mL triethylamine, add 2-furylamine (44mg, 0.45mmol) and 2 hydroxy pyrimidine (43mg, 0.45mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-4-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 36d (65mg, yellow semi-solid), productive rate: 73.8%.
MS?m/z(ESI)：660[M+1]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-4-aminomethyl phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(65mg 0.10mmol) is dissolved in the 1mL methylene dichloride 8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(3-methoxy propoxy)-4-aminomethyl phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 36d, stirs to add 2mL concentrated hydrochloric acid and 1 down, 4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (10mL * 3), merge organic phase, successively water (5mL * 2) and saturated sodium-chloride washing (5mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(3-methoxy propoxy)-4-aminomethyl phenyl) azelaoyl amine 36 (30mg, white solid), productive rate: 54.5%.
MS?m/z(ESI)：560[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.06(m，2H)，7.65(t，J＝4.2Hz，1H)，7.39(s，1H)，6.73(m，2H)，6.26(m，2H)，4.55(dd，J＝16Hz，6.4Hz，1H)，4.33(dd，J＝16Hz，4.8Hz，1H)，4.15(t，J＝6.0Hz，2H)，3.72(t，J＝8.0Hz，1H)，3.61(t，J＝6.0Hz，2H)，3.41(s，3H)，3.04(br.s，1H)，2.46(m，2H)，2.31(m，4H)，2.11(m，3H)，1.98(t，J＝12Hz，1H)，1.76～1.92(m，3H)，1.33～1.60(m，2H)，1.33(m，2H)，0.94(m，12H)
Embodiment 37
(2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(2-methoxy ethoxy) phenyl) azelaoyl amine
Figure G2010100039198D00871
Figure G2010100039198D00881
The first step
4-bromo-1-(2-methoxy ethoxy)-2-oil of mirbane
With 5-bromo-2-nitrophenols 37a (650mg, 2.98mmol) be dissolved in 6mL N, in the dinethylformamide, add potassiumiodide (247mg, 1.49mmol) and Anhydrous potassium carbonate (453mg 3.28mmol), dropwise adds 1-bromo-2-methoxyl group-ethane (456mg, 3.28mmol), 110 ℃ of following stirring reactions 6 hours.The reaction solution concentrating under reduced pressure, add 10mL water, with ethyl acetate extraction (20mL * 3), water (10mL * 2) and saturated nacl aqueous solution washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates and obtains title product 4-bromo-1-(2-methoxy ethoxy)-2-oil of mirbane 37b (720mg, yellow solid) crude product, productive rate: 87.0%.
Second step
2-(2-methoxy ethoxy) aniline
(360mg 1.30mmol) is dissolved in the 5mL methyl alcohol, adds palladium/carbon (18mg, 10%), hydrogen exchange three times, stirring reaction 24 hours with 4-bromo-1-(2-methoxy ethoxy)-2-oil of mirbane 37b.Filter, with ethyl acetate extraction (20mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (10mL * 2) and saturated sodium-chloride washing (10mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 2-(2-methoxy ethoxy) aniline 37c (152mg with the silica gel column chromatography purifying, brown oil), productive rate: 70.0%.
The 3rd step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(2-methoxy ethoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester
Will (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (116mg, 0.30mmol) be dissolved in the 5mL acetonitrile, add diisopropylethylamine (0.15mL, 0.30mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (114mg, 0.30mmol), stirring reaction 10 minutes, (50mg 0.30mmol), continues to stir 12 hours to add 2-(2-methoxy ethoxy) aniline 37c.The reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(2-methoxy ethoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 37d (80mg, yellow semi-solid), productive rate: 50.0%.
MS?m/z(ESI)：535[M+1]
The 4th step
(3R, 5S, 6S, 8S)-8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(2-methoxy ethoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl)-5-(2-(2-methoxy ethoxy) phenyl amino)-5-oxo amyl group carboxylamine tertiary butyl ester 37d (80mg, 0.15mmol) be dissolved in the 1mL triethylamine, add 2-furylamine (44mg, 0.45mmol) and 2 hydroxy pyrimidine (43mg, 0.45mmol), 80 ℃ of following stirring reactions 12 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(2-methoxy ethoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 37e (69mg, yellow semi-solid), productive rate: 73.0%.
MS?m/z(ESI)：632[M+1]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(2-methoxy ethoxy) phenyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(65mg 0.10mmol) is dissolved in the 1mL methylene dichloride 8-((furans-2-ylmethyl) carbamyl)-6-hydroxyl-3-sec.-propyl-1-(2-(2-methoxy ethoxy) phenyl amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 37e, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution adjusting pH and be about 8, with dichloromethane extraction (10mL * 3), merge organic phase, successively water (5mL * 2) and saturated sodium-chloride washing (5mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl-N 9-(2-(2-methoxy ethoxy) phenyl) azelaoyl amine 37 (28mg, faint yellow solid), productive rate: 51.6%.
MS?m/z(ESI)：532[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.37(b?r.s，1H)，8.33(d，J＝8.0Hz，1H)，7.37(s，1H)，7.03(m，3H)，6.61(br.s，1H)，6.32(s，1H)，6.26(s，1H)，4.51(dd，J＝15.6Hz，5.6Hz，1H)，4.42(dd，J＝15.6Hz，4.2Hz，1H)，4.20(t，J＝4.4Hz，2H)，3.78(t，J＝4.4Hz，2H)，3.50(s，3H)，3.29(br.t，J＝8Hz，1H)，2.61(m，1H)，2.46(dd，J＝15.6Hz，4Hz，1H)，2.26(m，1H)，2.15(br.s，1H)，1.87(m，1H)，1.78(m，2H)，1.56(m，1H)，1.43(m，3H)，1.33(m，3H)，0.94(m，12H)
Embodiment 38
(2S, 4S, 5S, 7R)-5-amino-N 1-((S)-1-cyclohexyl ethyl)-N 9-(3-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00891
Figure G2010100039198D00901
The first step
(3R, 5S, 6S, 8S)-8-((S)-1-cyclohexyl ethylamino formyl)-1-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 7c (28mg, 0.050mmol) be dissolved in the 1mL triethylamine, add (S)-1-cyclohexyl-ethamine (19mg, 0.15mmol) and 2 hydroxy pyrimidine (14mg, 0.15mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-((S)-1-cyclohexyl ethylamino formyl)-1-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 38a (28mg, yellow semi-solid), productive rate: 81.0%.MS?m/z(ESI)：716[M+23]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-((S)-1-cyclohexyl ethyl)-N 9-(3-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(24mg 0.035mmol) is dissolved in the 1mL methylene dichloride 8-((S)-1-cyclohexyl ethylamino formyl)-1-(3-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 38a, adds 2mL concentrated hydrochloric acid and 1, the 4-dioxane (V/V=1: 1) mixing solutions, continued stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, successively water (10mL * 2) and saturated sodium-chloride washing (10mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-((S)-1-cyclohexyl ethyl)-N 9-(3-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 38 (17mg, yellow solid), productive rate: 80.5%.
MS?m/z(ESI)：594[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.72(b?r.s，1H)，8.07(d，J＝8.4Hz，1H)，6.98(m，2H)，6.82(m，1H)，6.29(s，2H)，4.22(t，J＝5.6Hz，2H)，3.85(m，1H)，3.72(t，J＝5.6Hz，1H)，3.52(br.s，1H)，3.43(s，3H)，2.77(br.s，1H)，2.52(d，J＝15.2Hz，1H)，2.15～2.32(m，2H)，1.95～2.14(m，3H)，1.40～1.92(m，12H)，1.0～1.39(m，10H)，0.90(m，12H)
Embodiment 39
(2S, 4S, 5S, 7R)-5-amino-N 1-((S)-1-cyclohexyl ethyl)-N 9-(4-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00911
The first step
(3R, 5S, 6S, 8S)-8-((S)-1-cyclohexyl ethylamino formyl)-1-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 8c (32mg, 0.056mmol) be dissolved in the 1mL triethylamine, add (S)-1-cyclohexyl-ethamine (22mg, 0.17mmol) and 2 hydroxy pyrimidine (16mg, 0.17mmol), 80 ℃ of following stirring reactions 16 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-and 8-((S)-1-cyclohexyl ethylamino formyl)-1-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 39a (28mg, faint yellow solid), productive rate: 72.0%.MS?m/z(ESI)：716[M+23]
Second step
(2S, 4S, 5S, 7R)-5-amino-N 1-((S)-1-cyclohexyl ethyl)-N 9-(4-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(28mg 0.040mmol) is dissolved in the 1mL methylene dichloride 8-((S)-1-cyclohexyl ethylamino formyl)-1-(4-fluoro-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 39a, stirs to add 2mL concentrated hydrochloric acid and 1 down, 4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, successively water (10mL * 2) and saturated sodium-chloride washing (10mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 1-((S)-1-cyclohexyl ethyl)-N 9-(4-fluoro-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 39 (19mg, yellow solid), productive rate: 80.0%.
MS?m/z(ESI)：594[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.18(t，J＝8Hz，1H)，7.97(s，1H)，6.67(m，2H)，6.27(m，1H)，4.18(t，J＝6.4Hz，2H)，3.87(m，1H)，3.61(t，J＝6.0Hz，2H)，3.54(m，1H)，3.43(s，3H)，3.40(d，J＝3.2Hz，1H)，2.81(m，1H)，2.52(d，J＝15.6Hz，1H)，2.05～2.43(m，5H)，1.44～1.92(m，12H)，1.07～1.39(m，10H)，0.90(m，12H)
Embodiment 40
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-bromo-2-(3-methoxy propoxy) phenyl)-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D00921
The first step
4-bromo-1-(3-methoxy propoxy)-2-oil of mirbane
With 5-bromo-2-nitrophenols 37a (2.18g, 0.010mol) and salt of wormwood (3.45g 0.025mol) is dissolved in the anhydrous N of 80mL, in the dinethylformamide, add 3-methoxy-propyl 4-tosylate 1b (2.93g, 0.012mol), 115 ℃ of following stirring reactions 12 hours.With 100mL water washing reaction solution, ethyl acetate extraction (100mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 4-bromo-1-(3-methoxy propoxy)-2-oil of mirbane 40a (1.13g with the silica gel column chromatography purifying, yellow solid), productive rate: 39.0%.
Second step
5-bromo-2-(3-methoxy propoxy) aniline
With 4-bromo-1-(3-methoxy propoxy)-2-oil of mirbane 40a (580mg 2.01mmol) is dissolved in the 30mL acetonitrile, add iron powder (782mg, 14.02mmol), dropwise add acetate (1.80g, 30.01mmol), stirring reaction 12 hours.Filter, add the 1M sodium hydroxide solution and regulate pH greater than 10.With ethyl acetate extraction (60mL * 3), merge organic phase, water (20mL * 2) and saturated sodium-chloride washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 5-bromo-2-(3-methoxy propoxy) aniline 40b (500mg, yellow solid), productive rate: 96.2%.
The 3rd step
(1S, 3R)-5-(5-bromo-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester
With benzotriazole-1-three (three methylamino-s)-hexafluoro phosphorus (290mg, 1.14mmol) and triethylamine (115mg, 1.14mmol) be dissolved in the 5mL methylene dichloride, stirring reaction 1 hour, and adding 5mL (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (293mg, 0.76mmol) dichloromethane solution and 5-bromo-2-(3-methoxy propoxy) aniline 40b (297mg, 1.14mmol), stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1S, 3R)-5-(5-bromo-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 40c (150mg, yellow thick liquid), productive rate: 31.6%.
MS?m/z(ESI)：649[M+23]
The 4th step
(3R, 5S, 6S, 8S)-1-(5-bromo-2-(3-methoxy propoxy) phenyl amino)-8-(furans-2-ylmethyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-bromo-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 40c (144mg, 0.23mmol) be dissolved in the 1.5mL triethylamine, add 2-furylamine (67mg, 0.69mmol) and 2 hydroxy pyrimidine (65.6mg, 0.65mmol), 80 ℃ of following stirring reactions 16 hours.Concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (3R, 5S, 6S, 8S) 1-(5-bromo-2-(3-methoxy propoxy) phenyl amino)-8-(furans-2-ylmethyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 40d (83mg, yellow solid), productive rate: 50.0%.
MS?m/z(ESI)：746[M+23]
The 5th step
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-bromo-2-(3-methoxy propoxy) phenyl)-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-(72mg 0.10mmol) is dissolved in the 1mL methylene dichloride 1-(5-bromo-2-(3-methoxy propoxy) phenyl amino)-8-(furans-2-ylmethyl carbamyl)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decane-5-aminocarbamic acid tertiary butyl ester 40d, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, successively water (10mL * 2) and saturated sodium-chloride washing (10mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(5-bromo-2-(3-methoxy propoxy) phenyl)-N 1-(furans-2-ylmethyl)-4-hydroxyl-2,7-di-isopropyl azelaoyl amine 40 (32mg, deep yellow semisolid), productive rate: 50.0%.
MS?m/z(ESI)：624[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.42(d，J＝2.4Hz，1H)，8.16(s，1H)，7.43(m，1H)，4.41(s，1H)，7.17(dd，J＝8.8Hz，2.0Hz，1H)，6.79(d，J＝8.8Hz，1H)，6.30(m，2H)，4.55(dd，J＝15.0Hz，6.4Hz，1H)，4.38(dd，J＝15.0Hz，6.4Hz，1H)，4.16(t，J＝6.0Hz，2H)，3.70～3.50(m，3H)，3.41(s，3H)，3.03(m，1H)，2.51～2.41(m，3H)，2.16～2.07(m，3H)，1.92～1.83(m，3H)，1.70～1.51(m，2H)，0.94(m，12H)
Embodiment 41
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-yl) azelaoyl amine
Figure G2010100039198D00941
The first step
(1R, 4R)-4-(dibenzyl amino) hexalin
Will (1R, 4R)-4-Trans-4-Amino Cyclohexanol hydrochloride 41a (4.01g 26.40mmol) is dissolved in the 50mL acetonitrile, add sodium hydroxide solution (3.69g, 92.30mmol) and bromobenzyl 41b (67mg, 0.69mmol), 60 ℃ of following stirring reactions 12 hours.In reaction solution, add less water, concentrating under reduced pressure with ethyl acetate extraction (75mL * 3), merges organic phase, water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1R, 4R)-4-(dibenzyl amino) hexalin 41c (9.0g, white solid) crude product.
Second step
(1R, 4R)-N, N-dibenzyl-4-methoxyl group hexahydroaniline
Under the ice bath, will (1R, 4R)-(8.02g 27.01mmol) is dissolved in the 100mL tetrahydrofuran (THF) 4-(dibenzyl amino) hexalin 41c, the adding sodium hydride (1.30g, 32.50mmol), stirring reaction 40 minutes, (2.60mL 40.60mmol), continued stirring reaction 2 hours to drip methyl iodide.In reaction solution, add less water,, merge organic phase with ethyl acetate extraction (75mL * 3), water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1R, 4R)-N, N-dibenzyl-4-methoxyl group hexahydroaniline 41d (7.90g, colorless oil), productive rate: 94.0%.
The 3rd step
(1R, 4R)-4-methoxyl group hexahydroaniline
Will (1R, 4R)-N, (7.90g 0.025mol) be dissolved in the 100mL tetrahydrofuran (THF) N-dibenzyl-4-methoxyl group hexahydroaniline 41d, adds palladium/carbon (1.60g, 10%), hydrogen exchange three times, 45 ℃ of following stirring reactions 12 hours.Reacting liquid filtering, filtrate decompression concentrate, with the silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1R, 4R)-4-methoxyl group hexahydroaniline 41e (1.30g, colourless liquid), productive rate: 40.0%.
The 4th step
3-nitro-5,6,7,8-naphthane-2-alcohol
With 5,6,7, the 8-naphthane-(2.01g, 13.50mmol adopt known method Tetrahedron to 2-alcohol 41f
Letters, 35 (47), 8727-8730,1994 preparations and get) be dissolved in 67.5mL chloroform and Glacial acetic acid (V/V=2: 1) in the mixed solvent, adding 22.5mL concentrated nitric acid (0.91mL, glacial acetic acid solution 13.70mmol), stirring reaction 12 hours.In reaction solution, add 70mL water, concentrating under reduced pressure, add yellow soda ash and regulate pH to 10, water dichloromethane extraction (100mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, filters, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product 3-nitro-5,6 with the silica gel column chromatography purifying, 7,8-naphthane-2-alcohol 41g (1.40g, yellow solid), productive rate: 55.0%.
MS?m/z(ESI)：192[M-1]
The 5th step
6-(3-methoxy propoxy)-7-nitro-1,2,3, the 4-naphthane
With 3-nitro-5,6,7,8-naphthane-2-alcohol 41g (3.60g, 18.70mmol) and salt of wormwood (3.86g 30.01mmol) is dissolved in 15mL N, in the N-methylformamide, drip 3-methoxy-propyl 4-tosylate 1b (5.01g, 20.50mmol), 110 ℃ of following stirring reactions 6 hours.In reaction solution, add less water,, merge organic phase with ethyl acetate extraction (100mL * 3), anhydrous sodium sulfate drying is used in water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, filters, filtrate decompression concentrates, (eluent: the gained resistates system B of suitable proportion) obtains title product 6-(3-methoxy propoxy)-7-nitro-1,2 with the silica gel column chromatography purifying, 3,4-naphthane 41h (4.60g, brown oil), productive rate: 93.0%.
MS?m/z(ESI)：266[M+1]
The 6th step
3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-amine
With 6-(3-methoxy propoxy)-7-nitro-1,2,3, (4.60g 17.40mmol) is dissolved in the 10mL methyl alcohol 4-naphthane 41h, adds palladium hydroxide (0.50g, 10%), hydrogen exchange three times, stirring reaction 12 hours.Reacting liquid filtering, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product 3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-amine 41i (3.80g, brown oil), productive rate: 92.7%.
MS?m/z(ESI)：236[M+1]
The 7th step
(1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester
Will (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (819mg, 2.10mmol) be dissolved in the 10mL acetonitrile, add diisopropylethylamine (0.50mL, 1.20mmol) and benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (870mg, 2.10mmol), stirring reaction 10 minutes adds 3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-amine 41i (500mg, 2.10
Mmol), continued stirring reaction 24 hours.The reaction solution concentrating under reduced pressure, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-base is amino)-5-oxo amyl group carboxylamine tertiary butyl ester 41j (630mg, pale brown look oily matter), productive rate: 49.2%.
MS?m/z(ESI)：603[M+1]
The 8th step
(3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-1-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-base is amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-base is amino)-(120mg 0.20mmol) is dissolved in the 5mL triethylamine 5-oxo amyl group carboxylamine tertiary butyl ester 41j, adds (1R, 4R)-4-methoxyl group hexahydroaniline 41e (77mg, 0.60mmol) and 2 hydroxy pyrimidine (56.8mg, 0.60mmol), 80 ℃ of following stirring reactions 24 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent :) gained resistates, obtain title product (3R, 5S suitably than the system B that is listed as, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-1-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-base is amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 41k (81mg, white solid), productive rate: 70.4%.
MS?m/z(ESI)：732[M+1]
The 9th step
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-1-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-base is amino)-(81mg 0.11mmol) is dissolved in the 1mL methylene dichloride 9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 41k, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH,, merge organic phase with dichloromethane extraction (20mL * 3) greater than 7, water (10mL * 2) and saturated sodium-chloride washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-yl) azelaoyl amine 41 (53mg, white is semi-solid), productive rate: 76.0%.
MS?m/z(ESI)：632[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.07(s，1H)，7.91(s，1H)，6.73(d，J＝8.0Hz，1H)，6.64(s，1H)，4.14(t，J＝6.0Hz，2H)，3.75(m，2H)，3.62(t，J＝5.6Hz，2H)，3.42(s，3H)，3.32(s，3H)，3.14(br.s，1H)，2.96(br.s?1H)，2.73(br.s，3H)，2.55(d，J＝16.4Hz，1H)，2.26(m，2H)，2.13～1.50(m，22H)，0.92(m，12H)
Embodiment 42
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-ethyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl) azelaoyl amine
Figure G2010100039198D00971
The first step
4-ethyl-2-nitrophenols
With 4-ethylphenol 42a (20.01g, 0.16mol) be dissolved in 520mL water and ether (V/V=1: 1) in the mixed solvent, add salt of wormwood (18.21g, 0.18mol) and concentrated hydrochloric acid (26mL, 0.32mol), stirring reaction 24 hours.Concentrating under reduced pressure, with ethyl acetate extraction (500mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (100mL * 2) and saturated sodium-chloride washing (100mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 4-ethyl-2-nitrophenols 42b (25.74g with the silica gel column chromatography purifying, yellow oil), productive rate: 94.0%.
Second step
4-ethyl-1-(3-methoxy propoxy)-2-oil of mirbane
With 4-ethyl-2-nitrophenols 42b (10.01g 0.60mol) is dissolved in the 75mL 2-butanone, add salt of wormwood (20.70g, 0.15mol) and 3-methoxy-propyl 4-tosylate 1b (16.01g, 0.060mol), back flow reaction 24 hours.Reaction solution is poured in the 100mL water, with ethyl acetate extraction (200mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (100mL * 2) and saturated sodium-chloride washing (100mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 4-ethyl-1-(3-methoxy propoxy)-2-oil of mirbane 42c (9.65g with the silica gel column chromatography purifying, yellow oil), productive rate: 67.0%.
The 3rd step
5-ethyl-2-(3-methoxy propoxy) aniline
With 4-ethyl-1-(3-methoxy propoxy)-2-oil of mirbane 42c (9.61g 40.30mmol) is dissolved in the 150mL acetonitrile, add iron powder (18.01g, 322.60mmol) and Glacial acetic acid (48.00g, 802.01mmol), stirring reaction 24 hours.Regulate pH to 10 with the 1M sodium hydroxide solution, filter concentrating under reduced pressure, with ethyl acetate extraction (200mL * 3), merge organic phase, anhydrous sodium sulfate drying is used in water (100mL * 2) and saturated sodium-chloride washing (100mL * 2) successively, filter, filtrate decompression concentrates, and (eluent: the gained resistates system B of suitable proportion) obtains title product 5-ethyl-2-(3-methoxy propoxy) aniline 42d (7.20g with the silica gel column chromatography purifying, yellow oil), productive rate: 86.0%.
The 4th step
(1S, 3R)-5-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester
With (3R, 5S)-5-(tertbutyloxycarbonyl)-3-sec.-propyl-5-((2S, 4S)-and 4-sec.-propyl-5-oxo-tetrahydrofuran (THF)-2-yl) valeric acid 1j (800mg, 2.07mmol) be dissolved in the 30mL acetonitrile, add diisopropylethylamine (1.3mL, 3.01mmol) and benzotriazole-N, N, N ', and N '-tetramethyl-urea phosphofluoric acid ester (788mg, 0.27mmol), stirring reaction 10 minutes, (434mg 2.07mmol), continued stirring reaction 24 hours to add 5-ethyl-2-(3-methoxy propoxy) aniline 42d.The reaction solution concentrating under reduced pressure, with ethyl acetate extraction (100mL * 3), merge organic phase, water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography purifying (eluent: the gained resistates system B of suitable proportion), obtain title product (1S, 3R)-5-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 42e (800mg, yellow oil), productive rate: 67.0%.
The 5th step
(3R, 5S, 6S, 8S)-1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 42e (200mg, 0.35mmol) be dissolved in the 2mL triethylamine, add (1R, 4R)-4-methoxyl group hexahydroaniline 41e (136mg, 1.05mmol) and 2 hydroxy pyrimidine (100mg, 1.05mmol), 80 ℃ of following stirring reactions 24 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent :) gained resistates suitably than the system B that is listed as, obtain title product (3R, 5S, 6S, 8S)-1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 42f (150mg, yellow thick liquid), productive rate: 60.7%.
The 6th step
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-ethyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 42f (150mg, 0.20mmol) be dissolved in the 2mL methylene dichloride, add 4mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (50mL * 3), merge organic phase, successively water (20mL * 2) and saturated sodium-chloride washing (20mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(5-ethyl-2-(3-methoxy propoxy) phenyl)-4-hydroxyl-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl) azelaoyl amine 42 (85mg, faint yellow semisolid), productive rate: 66.0%.
MS?m/z(ESI)：606[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.14(s，2H)，6.92(d，J＝8.4Hz，1H)，6.86(d，J＝8.4Hz，1H)，6.75(m，1H)，4.16(t，J＝6.0Hz，2H)，3.78(m，1H)，3.64(m，1H)，3.62(t，J＝6.0Hz，1H)，3.49(s，3H)，3.36(s，3H)，3.12(br.s，1H)，2.91(br.s，1H)，2.62(q，J＝7.6Hz，2H)，2.52(d，J＝15.6Hz，1H)，2.31(m，2H)，2.12～1.82(m，10H)，1.60(m，2H)，1.40(m，4H)，1.35(t，J＝6.0Hz，3H)，1.05～0.95(m，12H)
Embodiment 43
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine fumarate
Figure G2010100039198D00991
The first step
(3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-(186mg 0.32mmol) is dissolved in the 2mL triethylamine 5-oxo amyl group carboxylamine tertiary butyl ester 20d, adds (1R, 4R)-4-methoxyl group hexahydroaniline 41e (122mg, 0.95mmol) and 2 hydroxy pyrimidine (90mg, 0.95mmol), 80 ℃ of following stirring reactions 24 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent :) gained resistates suitably than the system A that is listed as, obtain title product (3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 43a (137mg, faint yellow solid), productive rate: 60.4%.MS?m/z(ESI)：718[M+1]
Second step
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-6-hydroxyl-3-sec.-propyl-8-((1R, 4S)-4-methoxyl group cyclohexyl carboxyamide)-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-(137mg 0.19mmol) is dissolved in the 1mL methylene dichloride 9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 43a, adds 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH,, merge organic phase with dichloromethane extraction (20mL * 3) greater than 7, water (10mL * 2) and saturated sodium-chloride washing (10mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 43 (102mg, faint yellow semisolid), productive rate: 86.5%.
MS?m/z(ESI)：618[M+1]
The 3rd step
(2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine fumarate
Will (2S, 4S, 5S, 7R)-and 5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9(52mg 0.084mmol) is dissolved in the 2mL methyl alcohol-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 43b, and (5mg, 0.042mmol) stirring reaction is 10 minutes to add fumaric acid.The reaction solution concentrating under reduced pressure, obtain title product (2S, 4S, 5S, 7R)-5-amino-4-hydroxy-2,7-di-isopropyl-N 1-((1R, 4S)-4-methoxyl group cyclohexyl)-N 9-(3-(3-methoxy propoxy)-5,6,7,8-naphthane-2-yl) azelaoyl amine fumarate 43 (51mg, faint yellow solid), productive rate: 98.3%.
MS?m/z(ESI)：618[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.13(s，1H)，8.07(s，1H)，6.98(d，J＝7.6Hz，1H)，6.84(s，1H)，4.16(t，J＝6.0Hz，2H)，3.80～3.72(m，2H)，3.62(t，J＝6.0Hz，1H)，3.42(s，3H)，3.30(s，3H)，3.11(br.s，1H)，3.01(br.s，1H)，2.89～2.80(m，4H)，2.52(d，J＝15.6Hz，1H)，2.31(m，2H)，2.13～1.93(m，11H)，1.86～1.82(m，3H)，1.76～1.62(m，2H)，1.48～1.30(m，4H)，1.05～0.95(m，12H)
Embodiment 44
(2S, 4S, 5S, 7R)-5-amino-4-hydroxy-N 1-((1R, 4S)-the 4-hydroxy-cyclohexyl)-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
The first step
(1R, 4R)-4-(tertiary butyl dimethyl Si base) hexahydroaniline
Will (1R, 4R)-(500mg 3.30mmol) is dissolved in the 5mL methylene dichloride 4-Trans-4-Amino Cyclohexanol hydrochloride 41a, the adding TERT-BUTYL DIMETHYL CHLORO SILANE (1.50g, 9.90mmol), stirring reaction 20 minutes, the adding imidazoles (1.10g, 17.01mmol), stirring reaction 24 hours.In reaction solution, add less water, with ethyl acetate extraction (100mL * 3), merge organic phase, use 1M sodium hydroxide solution (50mL * 2), water (50mL * 2) and saturated sodium-chloride washing (50mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and (eluent: the gained resistates system A of suitable proportion) obtains title product (1R with the silica gel column chromatography purifying, 4R)-4-(tertiary butyl dimethyl Si base) hexahydroaniline 44a (800mg, faint yellow oily thing) crude product.
MS?m/z(ESI)：230[M+1]
Second step
(3R, 5S, 6S, 8S)-8-((1R, 4S)-4-(tertiary butyl dimethyl Si base) cyclohexyl carboxyamide)-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decyl-5-base is amino for 6-hydroxyl-3-sec.-propyl-1-
The formic acid tertiary butyl ester
With (1S, 3R)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-(200mg 0.34mmol) is dissolved in the 2mL triethylamine 5-oxo amyl group carboxylamine tertiary butyl ester 20d, adds (1R, 4R)-4-(tertiary butyl dimethyl Si base) hexahydroaniline 44a (312mg, 1.36mmol) and 2 hydroxy pyrimidine (97mg, 1.02mmol), 80 ℃ of following stirring reactions 24 hours.Concentrating under reduced pressure, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (3R, 5S, 6S, 8S)-8-((1R, 4S)-4-(tertiary butyl dimethyl Si base) cyclohexyl carboxyamide)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 44b (90mg, yellow oil), productive rate: 30.0%.
MS?m/z(ESI)：818[M+1]
The 3rd step
(3R, 5S, 6S, 8S)-6-hydroxyl-8-((1R, 4S)-4-hydroxy-cyclohexyl carbamyl)-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (3R, 5S, 6S, 8S)-8-((1R, 4S)-4-(tertiary butyl dimethyl Si base) cyclohexyl carboxyamide)-6-hydroxyl-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 44b (135mg, 0.17mmol) be dissolved in the 3mL tetrahydrofuran (THF), add tetrabutyl ammonium fluoride (130mg, 0.41mmol), 50 ℃ of following stirring reactions 1 hour.Add less water, with dichloromethane extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated sodium-chloride washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (3R, 5S, 6S, 8S)-6-hydroxyl-8-((1R, 4S)-4-hydroxy-cyclohexyl carbamyl)-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 44c (90mg, yellow solid), productive rate: 77.0%.
MS?m/z(ESI)：704[M+1]
The 4th step
(2S, 4S, 5S, 7R)-5-amino-4-hydroxy-N 1-((1R, 4S)-the 4-hydroxy-cyclohexyl)-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-6-hydroxyl-8-((1R, 4S)-4-hydroxy-cyclohexyl carbamyl)-3-sec.-propyl-1-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-base is amino)-(90mg 0.13mmol) is dissolved in the 2mL methylene dichloride 9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 44e, adds 4mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, successively water (10mL * 2) and saturated sodium-chloride washing (10mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: the gained resistates system A of suitable proportion), obtain title product (2S, 4S, 5S, 7R)-5-amino-4-hydroxy-N 1-((1R, 4S)-the 4-hydroxy-cyclohexyl)-2,7-di-isopropyl-N 9-(6-(3-methoxy propoxy)-2,3-dihydro-1H-indenes-5-yl) azelaoyl amine 44 (25mg, white is semi-solid), productive rate: 33.0%.
MS?m/z(ESI)：604[M+1]
1H?NMR(400MHz，CDCl 3，ppm)：δ8.5(b?r.s，1H)，8.12(br.s，1H)，6.90(b?r.s，1H)，4.19(m，2H)，3.74～3.59(m，4H)，3.47(s，2H)，3.37(s，3H)，2.99～2.84(m，4H)，2.43～2.07(m，3H)，2.03～1.79(m，15H)，1.43～1.34(m，3H)，0.92(m，12H)
Embodiment 45
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-ethyl-2-(3-methoxy propoxy) phenyl)-4-hydroxy-n 1-((1R, 4S)-the 4-hydroxy-cyclohexyl)-2,7-di-isopropyl azelaoyl amine
Figure G2010100039198D01031
The first step
(3R, 5S, 6S, 8S)-8-((1R, 4S)-4-(tertiary butyl dimethyl Si base) cyclohexyl carboxyamide)-1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (1S, 3R)-5-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-3-sec.-propyl-1-((2S, 4S)-4-sec.-propyl-5-oxo-tetrahydrofuran-2-yl)-5-oxo amyl group carboxylamine tertiary butyl ester 42e (200mg, 0.35mmol) be dissolved in the 2mL triethylamine, add (1R, 4R)-4-(tertiary butyl dimethyl Si base) hexahydroaniline 44a (348mg, 1.23mmol) and 2 hydroxy pyrimidine (100mg, 1.05mmol), 80 ℃ of following stirring reactions 24 hours.The reaction solution concentrating under reduced pressure, with thin-layer chromatography purifying (eluent :) gained resistates suitably than the system B that is listed as, obtain title product (3R, 5S, 6S, 8S)-8-((1R, 4S)-4-(tertiary butyl dimethyl Si base) cyclohexyl carboxyamide)-1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 45a (90mg, yellow oil), productive rate: 32.0%.
Second step
(3R, 5S, 6S, 8S)-1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-8-((1R, 4S)-4-hydroxy-cyclohexyl carbamyl)-3-sec.-propyl-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester
With (3R, 5S, 6S, 8S)-8-((1R, 4S)-4-(tertiary butyl dimethyl Si base) cyclohexyl carboxyamide)-(94mg 0.17mmol) is dissolved in the 3mL tetrahydrofuran (THF) 1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-3-sec.-propyl-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 45a, adds tetrabutyl ammonium fluoride (110mg, 0.35mmol), stirring reaction 24 hours.Add less water, with dichloromethane extraction (50mL * 3), merge organic phase, water (20mL * 2) and saturated sodium-chloride washing (20mL * 2) successively, use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product (3R, 5S, 6S, 8S)-1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-8-((1R, 4S)-4-hydroxy-cyclohexyl carbamyl)-3-sec.-propyl-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 45b (60mg, yellow oil), productive rate: 75.0%.
The 3rd step
(2S, 4S, 5S, 7R)-5-amino-N 9-(5-ethyl-2-(3-methoxy propoxy) phenyl)-4-hydroxy-n 1-((1R, 4S)-the 4-hydroxy-cyclohexyl)-2,7-di-isopropyl azelaoyl amine
Under the ice bath, with (3R, 5S, 6S, 8S)-1-(5-ethyl-2-(3-methoxy propoxy) phenyl amino)-6-hydroxyl-8-((1R, 4S)-4-hydroxy-cyclohexyl carbamyl)-3-sec.-propyl-9-methyl isophthalic acid-oxo decyl-5-aminocarbamic acid tertiary butyl ester 45b (60mg, 0.087mmol) be dissolved in the 1mL methylene dichloride, add 2mL concentrated hydrochloric acid and 1,4-dioxane (V/V=1: 1) mixing solutions, stirring reaction 2 hours.In reaction solution, add saturated sodium bicarbonate solution and regulate pH greater than 7, with dichloromethane extraction (20mL * 3), merge organic phase, successively water (10mL * 2) and saturated sodium-chloride washing (10mL * 2), use anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with thin-layer chromatography purifying (eluent: suitably than the system A that is listed as) gained resistates, obtain title product (2S, 4S, 5S, 7R)-5-amino-N 9-(5-ethyl-2-(3-methoxy propoxy) phenyl)-4-hydroxy-n 1-((1R, 4S)-the 4-hydroxy-cyclohexyl)-2,7-di-isopropyl azelaoyl amine 45 (33mg, white solid), productive rate: 64.0%.
MS?m/z(ESI)：592[M+1]
1H?NMR(400MHz，CDCl 3，TMS，ppm)：δ8.53～80.4(m，3H)，7.15～6.82(m，2H)，4.18(m，2H)，3.92～3.47(m，4H)，3.27(s，3H)，3.00～2.57(m，3H)，2.53(m，2H)，2.39～2.23(m，3H)，2.07～1.58(m，11H)，1.49～1.20(m，6H)，1.05～0.80(m，12H)
Test case:
Biological assessment
Test case 1, compound suppress the renin activity test
Following method is to be used for measuring the inhibition ability of invention compound to the feritin protease activity.The half-inhibition concentration IC of each compound 50(enzymic activity is suppressed to 50% o'clock compound concentrations of surveying) is to be used for measuring with the substrate of the enzyme Mixed Stationary amount of fixed amount and the testing compound of different concns.
The compounds of this invention suppresses active mensuration to feritin
Material:
1. black 96 orifice plates (Greiner bio-one#655087)
2.10X damping fluid
The 1X damping fluid
50mM?Tris-HCl
100mMNaCl
pH?8.0
(Cayman#l0006870)
3.Renin enzyme (sigma-aldrich#R2779)
4.Renin substrate (Cayman#100068720)
5.ddH 2O
(6.DMSO traditional Chinese medicines #30072418)
Method:
Undertaken by following working order:
1. with 50% DMSO (DMSO: ddH 2O, 1: 1) compound is diluted in advance the final concentration that needs.
2. use dd H 2O is diluted to the 1X damping fluid with the 10X damping fluid.37 ℃ of preheating 1X damping fluids.
(3.Blank blank group)-add 10 μ L substrates, 80 μ L 1X damping fluids, 5 μ L 50%DMSO are established the contrast of multiple hole to every hole.
4.Negative control (100% active control group)-add 10 μ L substrates, 75 μ L1X damping fluids, 5 μ L50%DMSO establish the contrast of multiple hole to every hole.
(5.Sample test-compound group)-add 10 μ L substrates, 75 μ L1X damping fluids, 5 μ L compounds (being dissolved in 50%DMSO) are established the contrast of multiple hole to every hole.
6. dilute the Renin enzyme to 8.33ng/ μ L with the 1X damping fluid.
7. add 5 μ L Renin to Negative control reacting holes and Sample reacting hole and start reaction.Micro oscillator shake 10 second mixing, shrouding film shrouding was hatched 90 minutes for 37 ℃.
8. remove the shrouding film, under excitation wavelength 335～345nm and emission wavelength 485～510nm condition, read fluorescent value.
Inhibiting rate calculates:
IR(％)＝100-100*(S-B)/(N-B)
S=adds the fluorescent value of the reacting hole of test compounds
The fluorescent value of N=negative control reacting hole
The fluorescent value of B=blank well
IC 50Value can be calculated by the IR value of test compounds under concentration gradient and get.
The activity of The compounds of this invention
The biochemical activity of The compounds of this invention is measured by above test, the IC that records 50Value sees the following form.
The embodiment compound IC 50Value (nM)
1 19
7 14
8 18
11 18
13 8
14 17
16 6
17 11
18 6
19 13
20 13
21 16
23 19
25 6
41 15
42 5
43 7
44 18
45 13
Conclusion: the IC of compound of the present invention 50Value is 6～28nM, and it all has inhibition significantly active to feritin proteolytic enzyme.
Pharmacokinetics is estimated
The pharmacokinetics test of test case 2, The compounds of this invention
1, summary
With the rat is animal subject, uses the LC/MS/MS method and has measured rat oral gavage and give the drug level in the different moment blood plasma behind embodiment 14,21 and 43 compounds.The research The compounds of this invention is estimated its characteristics of pharmacokinetics in the pharmacokinetics in rats behavior.
2, testing program
2.1 test drug
Embodiment 14, embodiment 21 and embodiment 43 compounds.
2.2 experimental animal
12 of healthy adult SD rats, male and female half and half, 4 every group, available from west, Shanghai pul-Bi Kai laboratory animal company limited, animal production licence number: SCXK (Shanghai) 2008-0016.
2.3 medicine preparation
Take by weighing a certain amount of medicine, add 0.5% sodium cellulose glycolate and be mixed with the 3.0mg/mL suspension liquid.
2.4 administration
12 of SD rats, male and female half and half, 4 every group, difference gastric infusion behind the overnight fasting, dosage is 30.0mg/kg.
3. operation
20 of SD rats, male and female half and half, gastric infusion after one night of fasting, dosage is 30.0mg/kg, embodiment 14, embodiment 21 and embodiment 43 compounds before administration and administration after 0.5,1.0,2.0,3.0,4.0,6.0,8.0,12.0,24.0,36.0,48.0, placed the heparinization test tube by eye socket blood sampling 0.2mL in 72.0 hours, 4 ℃, 10000 rev/mins centrifugal 10 minutes separated plasmas, in-20 ℃ of preservations, feed in 2 hours after the administration.
Measure the testing compound in the rat plasma behind the medicine gastric infusion of different concns: draw each rat plasma 50 μ L constantly behind the medicine, add inner mark solution 50 μ L, methyl alcohol 100 μ L, vortex mixed 3 minutes, centrifugal 10 minutes (13500 rev/mins), plasma sample are got supernatant liquor 10 μ L and are carried out the LC/MS/MS analysis.
4, pharmacokinetic parameter result
The pharmacokinetic parameter of The compounds of this invention is as follows:
Conclusion: the medicine of The compounds of this invention is good for absorbing, and has tangible pharmacokinetics advantage.

Claims (15)

  1. Compound shown in the general formula (I) or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt:
    Figure F2010100039198C00011
    Wherein:
    X is selected from CH or N;
    R 1And R 2Be selected from independently of one another hydrogen atom, halogen, alkyl, alkoxyl group or-COR 4, wherein said alkyl or alkoxyl group are optional further to be replaced by one or more substituting groups that are selected from halogen, alkoxyl group, cycloalkyl or Heterocyclylalkyl;
    Perhaps, R 1And R 2Coupled atom forms 3～8 yuan of cyclic groups together, wherein said 3～8 yuan of rings contain 0～2 two key, contain 0～2 N, O or S (O) n heteroatoms, and described 3～8 yuan of rings are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, alkoxyl group or carbonyl;
    R 3Be selected from alkyl or cycloalkyl, wherein said alkyl or cycloalkyl optional further by one or more be selected from alkoxyl group, halogen, hydroxyl, cyano group, cycloalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters substituting group replace;
    R 4Be selected from alkyl or aryl;
    R 5And R 6Independently be selected from hydrogen atom or alkyl separately;
    M is 2 or 3; And
    N is 0,1 or 2.
  2. 2. compound according to claim 1 or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt, wherein said compound comprises:
    Figure F2010100039198C00012
    Figure F2010100039198C00021
    Figure F2010100039198C00031
  3. 3. the compound shown in the general formula (IA), described compound is the intermediate of synthetic general formula as claimed in claim 1 (I) compound:
    Figure F2010100039198C00032
    Wherein:
    X is selected from CH or N;
    R 1And R 2Be selected from independently of one another hydrogen atom, halogen, alkyl, alkoxyl group or-COR 4, wherein said alkyl or alkoxyl group are optional further to be replaced by one or more substituting groups that are selected from halogen, alkoxyl group, cycloalkyl or Heterocyclylalkyl;
    Perhaps, R 1And R 2Coupled atom forms 3～8 yuan of rings together, wherein said 3～8 yuan of rings contain 0～2 two key, contain 0～2 N, O or S (O) n heteroatoms, and described 3～8 yuan of rings are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, alkoxyl group or carbonyl;
    R 4Be selected from alkyl or aryl;
    M is 2 or 3;
    N is 0,1 or 2; And
    PG is the amido protecting group; wherein said amido protecting group is selected from tert-butoxycarbonyl, carbobenzoxy-(Cbz), ethanoyl, trifluoroacetyl group, formyl radical, p-toluenesulfonyl, trityl, phthalimide-based or 2-xenyl-2-third oxygen carbonyl, is preferably tert-butoxycarbonyl.
  4. 4. compound according to claim 3, wherein said compound comprises:
    Figure F2010100039198C00051
  5. 5. method for preparing as claim 3 or 4 described general formula (IA) compounds, this method comprises:
    Figure F2010100039198C00052
    Lactone a is in the presence of catalyzer, and oxidized dose of oxidation obtains compound b;
    Wherein said catalyzer is selected from ruthenium chloride, and ruthenium dioxide or ruthenium tetroxide are preferably ruthenium chloride; Described oxygenant is selected from: periodate, hypochlorite, ozone or hydrogen peroxide are preferably periodate;
    Figure F2010100039198C00053
    Compound b and substituted aromatic amines c reaction obtain general formula compound (IA);
    Wherein X, R 1, R 2, m and PG definition as described in the claim 3, and R 7And R 8Independently be selected from hydrogen atom or alkyl separately.
  6. 6. the compound shown in the general formula (IB), described compound is the intermediate of synthetic general formula as claimed in claim 1 (I) compound:
    Figure F2010100039198C00054
    Wherein:
    X is selected from CH or N;
    R 1And R 2Be selected from independently of one another hydrogen atom, halogen, alkyl, alkoxyl group or-COR 4, wherein said alkyl or alkoxyl group are optional further to be replaced by one or more substituting groups that are selected from halogen, alkoxyl group, cycloalkyl or Heterocyclylalkyl;
    Perhaps, R 1And R 2Coupled atom forms 3～8 yuan of rings together, wherein said 3～8 yuan of rings contain 0～2 two key, contain 0～2 N, O or S (O) n heteroatoms, and described 3～8 yuan of rings are optional is further replaced by one or more substituting groups that are selected from alkyl, halogen, alkoxyl group or carbonyl;
    R 3Be selected from alkyl or cycloalkyl, wherein said alkyl or cycloalkyl optional further by one or more be selected from alkoxyl group, halogen, hydroxyl, cyano group, cycloalkyl, aryl, heteroaryl ,-SO 2R 4,-SO 2NR 5R 6,-COR 4,-CONR 5R 6,-NR 5R 6, carboxylic acid or carboxylicesters substituting group replace;
    R 4Be selected from alkyl or aryl;
    R 5And R 6Independently be selected from hydrogen atom or alkyl separately;
    M is 2 or 3;
    N is 0,1 or 2; And
    G is the silica-based protecting group of hydroxyl, and that the silica-based protecting group of wherein said hydroxyl is selected from is trimethyl silicon based, triethyl is silica-based, tertiary butyl dimethyl is silica-based, triisopropylsilyl or tert-butyl diphenyl are silica-based.
  7. 7. compound according to claim 6, wherein said compound comprises:
    Figure F2010100039198C00061
  8. 8. method for preparing as claim 6 or 7 described general formula (IB) compounds, this method comprises:
    Figure F2010100039198C00062
    Compound d is sloughed prothetic group, obtains Verbindung;
    Figure F2010100039198C00063
    Verbindung adds diazomethane after generating acyl chlorides under alkaline condition with under thionyl chloride or the phosphorus oxychloride condition, then with silver suboxide, yellow soda ash and Sulfothiorine reaction generate compound f;
    Figure F2010100039198C00071
    Compound f and substituted aromatic amines c reaction obtain compound g;
    Figure F2010100039198C00072
    The lactonic ring open loop of compound g obtains compound h;
    Figure F2010100039198C00073
    Compound h and formula R 3NH 2Amine have reaction down, obtain general formula compound (IB);
    Wherein: X, R 1～R 3, m and G definition as described in the claim 6;
    Aux is a prothetic group, is selected from the ephedrine derivative, the oxazolidone derivative, and the crassitude ketone derivatives, carbohydrate, cycloalcohol or cyclic amine, described prothetic group preferably includes:
  9. 9. method for preparing general formula as claimed in claim 1 or 2 (I) compound, this method comprises:
    Figure F2010100039198C00081
    General formula compound (IA) and formula R 3NH 2Amine reaction, under suitable condition, slough the protecting group PG of amido then, obtain general formula (I) compound;
    X wherein, R 1～R 3With the definition of m according to claim 1, and the definition of PG is as described in the claim 3.
  10. 10. method for preparing general formula as claimed in claim 1 or 2 (I) compound, this method comprises:
    Figure F2010100039198C00082
    Compound (IB) is sloughed the silica-based protecting group G of hydroxyl under suitable condition, then diazo is reduced into amino, obtains general formula (I) compound;
    X wherein, R 1～R 3With the definition of m according to claim 1, and the definition of G is as described in the claim 6.
  11. 11. pharmaceutical composition, its contain the compound as claimed in claim 1 or 2 for the treatment of effective dose or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt, and pharmaceutically useful carrier or vehicle.
  12. 12. compound as claimed in claim 1 or 2 or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt, wherein pharmaceutically useful salt is compound and is selected from following sour formed salt: oxysuccinic acid, lactic acid, toxilic acid, hydrochloric acid, methylsulfonic acid, sulfuric acid, phosphoric acid, citric acid, fumaric acid, acetate or trifluoroacetic acid are preferably fumaric acid.
  13. 13. compound as claimed in claim 1 or 2 or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt, the purposes of pharmaceutical composition as claimed in claim 11 in the medicine of preparation treatment and renin activity diseases associated.
  14. 14. purposes according to claim 13, wherein said and renin activity diseases associated is selected from: hypertension, atherosclerosis, the instability mode coronary syndrome, congestive heart failure, myocardial hypertrophy, myocardial fibrosis, infraction back myocardosis, the instability mode coronary syndrome, diastolic dysfunction, chronic nephropathy, hepatic fibrosis, the complication that diabetes cause, coronary artery disease, the restenosis of postangioplasty, eye-chamber pressure raises, glaucoma, the abnormal vascular growth, hyperaldosteronism, cognitive impairment, alzheimer's disease, dull-witted, anxiety state or cognitive disorders, the complication that wherein said diabetes cause comprises ephrosis, vascular disease and neuropathy.
  15. 15. compound as claimed in claim 1 or 2 or its tautomer, racemic modification, enantiomer, diastereomer, and composition thereof form, and pharmaceutically useful salt, the purposes of pharmaceutical composition as claimed in claim 11 in the medicine of preparation renin inhibitor.
CN2010100039198A 2009-11-16 2010-01-13 5-amino-4-hydroxy-N-aryl azelamide derivatives as well as preparation methods and medical applications thereof Pending CN102060732A (en)

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CN103304404A (en) * 2013-05-30 2013-09-18 万华化学集团股份有限公司 Preparation method of 2,2-bis(hydroxymethyl) butyrate
CN104016947A (en) * 2014-05-16 2014-09-03 南通常佑药业科技有限公司 Method for preparing aliskiren intermediate
CN104387299A (en) * 2014-10-23 2015-03-04 凯莱英医药集团（天津）股份有限公司 Method for preparing 4-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-benzene butyl]-N-isobutyl benzsulfamide
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CN103145585B (en) * 2011-12-07 2015-08-19 上海医药工业研究院 A kind of preparation method of 2,2-dimethyl malonamide nitrile
CN103145585A (en) * 2011-12-07 2013-06-12 上海医药工业研究院 Preparation method for 2, 2-dimethyl cyano acetamide
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CN104016947A (en) * 2014-05-16 2014-09-03 南通常佑药业科技有限公司 Method for preparing aliskiren intermediate
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CN104387299B (en) * 2014-10-23 2016-08-17 凯莱英医药集团（天津）股份有限公司 The preparation method of 4-amino-N-[(2R, 3S)-3-amino-2-hydroxyl-4-benzene butyl]-N-isobutyl-benzene sulfonamide
CN107824180A (en) * 2017-08-25 2018-03-23 昆山普瑞凯纳米技术有限公司 A kind of preparation method of load-type nanometer metal catalyst for levulic acid hydrogenation
CN112573990A (en) * 2019-09-29 2021-03-30 沈阳中化农药化工研发有限公司 Preparation method of 4-halogenated-3-fluorotoluene
CN112573990B (en) * 2019-09-29 2022-05-06 沈阳中化农药化工研发有限公司 Preparation method of 4-halogenated-3-fluorotoluene
CN114315749A (en) * 2021-12-13 2022-04-12 湖南华腾医药有限公司 Method for synthesizing aliskiren intermediate by continuous flow microreactor
CN114315749B (en) * 2021-12-13 2024-04-26 湖南华腾医药有限公司 Method for synthesizing aliskiren intermediate by continuous flow microreactor
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