CN102206206A - Azabicyclooctane hydroximic acid derivatives, preparation method thereof, and application thereof in medicament - Google Patents

Azabicyclooctane hydroximic acid derivatives, preparation method thereof, and application thereof in medicament Download PDF

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CN102206206A
CN102206206A CN201010137007XA CN201010137007A CN102206206A CN 102206206 A CN102206206 A CN 102206206A CN 201010137007X A CN201010137007X A CN 201010137007XA CN 201010137007 A CN201010137007 A CN 201010137007A CN 102206206 A CN102206206 A CN 102206206A
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alkyl
methyl
pyrroles
aryl
cycloalkyl
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邓炳初
李心
陈阳
王斌
李相勤
藏捷
周颖
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 azabicyclooctane hydroximic acid derivatives, a preparation method thereof and application thereof in medicament, particularly novel azabicyclooctane hydroximic acid derivatives shown in general formula (I), a preparation method thereof, a medicament composition containing the derivatives and application of the azabicyclooctane hydroximic acid derivatives used as a therapeutic agent, particularly a disintegrin metalloproteinases (ADAMs) inhibitor.

Description

Azabicyclo-octane hydroxamic acid derivatives, its preparation method and in pharmaceutically application
Technical field
The present invention relates to azabicyclo-octane hydroxamic acid derivatives, its preparation method new shown in a kind of general formula (I) and contain this derivative pharmaceutical composition, with and as the purposes of therapeutical agent as disintegrin metalloprotein zymoprotein (ADAMs) inhibitor.
Background technology
Epidermal growth factor family acceptor (EGFR/ErbB family) participates in the adjusting of cell various physiological processes, comprises cell proliferation, differentiation and apoptosis.This receptor family is by four member composition: EGFR1 (Her-1 or ErbB1), Her-2 (neu or ErbB2), Her-3 (ErbB3) and Her-4 (ErbB4).There is multiple part corresponding simultaneously, comprises Urogastron EGF, transforming growth factor TGF α, heparin associativity growth factor-like part HG-EGF, amphiregulin amphiregulin or the like with this family receptors.ErbB receptor family member is activated in conjunction with back inductive family member's syndio form or special-shaped dimerization process by part, phosphorylation takes place in the tyrosine residues site of functional zone in the acceptor born of the same parents subsequently, and then the multiple signal cascade in the activating cells, final realization promotes biological functions such as cell growth.
ErbB receptor family member is closely related with the process of regulating cell growth and apoptosis, thereby makes it become the focal point of treatment tumor disease.Find after deliberation, in multiple common noumenal tumour, as mammary cancer, lung cancer, colorectal carcinoma and prostate cancer etc. can be observed unusual ErbB receptor signal.These anomalous signals are regulated and are usually expressed as: the overexpression of acceptor on the cytolemma, the amplification and the sudden change of the gene of coding acceptor or its part, and the rising of respective ligand expression level.These abnormal signals often corresponding the deterioration and the poor prognosis of tumor disease.For example, in the breast cancer treatment process, the EGFR of overexpression and EGF sample part cause tumour cell to be treated at hormone antagonist and show drug resistance, worsen and shift and poor prognosis (Gee J.M.W., etal.Breast Cancer Res., 5 (5): 223-224 (2003)).In addition, about 20%～30% patient with breast cancer, and ovarian cancer, nonsmall-cell lung cancer, colorectal carcinoma and pancreas patient exist the situation of tangible Her-2 acceptor overexpression, and especially for those showed nodus lymphoideus transferring rate male patient with breast cancer, the overexpression of her-2 acceptor was directly indicating relatively poor treatment result (Mosesson Y., et al.Semin.Cancer Biol., 14:262-270 (2004); Gschwind A., et al.Nat.Rev.Cancer, 4 (5): 361-70 (2004)).Make the relevant signal path of ErbB become the popular target spot of antitumor drug research and development and receive much concern based on above reason.If the drug main of existing exploitation is the humanized monoclonal antibody drug and the micromolecular kinase activity inhibitor of target spot with EGFR and Her-2.These medicines are by the tyrosine kinase activity of block ligand-acceptor interaction or inhibition ErbB family receptors, and then realization blocking-up ErbB Mediated Signal Transduction process (Paez J.G., et al.Science, 304:1497-1500 (2004)).Yet most of patient can produce drug resistance gradually in therapeutic process, thereby can't realize the long periods of treatment effect.Simultaneously, kinase inhibitor because of the toxic characteristics of its dose limitation also hinder its with optimum mass action in tumour cell.Therefore, exigence is developed the medicine that influences the ErbB signal path with different mechanism of action clinically.
Various cytokines or somatomedin part are at first all expressed in the membranin mode in its secretion process, and its born of the same parents' ectodomain hydrolysis under the effect of hydrolysising protease subsequently comes off, and then are used as functional molecular release.It is the basis that many film anchoring growth factors and cytokine participate in multiple secretion mode and realize the signal transduction process that the hydrolysis of this born of the same parents' ectodomain comes off.The process that the nearly cytolemma zone of this cell surface protein is hydrolyzed is called the outer cracking of born of the same parents, this process is mediated by the multiple protein enzyme, disintegrin metalloprotein enzyme family (ADAMs) is to be exactly the major protein enzyme (White J.M.Curr.Opin.Cell Biol., 15:598-606 (2003)) that mediates this hydrolysis shear history.ADAMs is under the jurisdiction of zinc bond proteolytic enzyme superfamily, also is referred to as and unloads enzyme (sheddeas) because it has the hydrolysis shearing action.ADAMs all has expression in raw animal and Mammals, have the ADAM homologous gene that surpasses 30 kinds to be detected at present, and 29 kinds are found in Mammals.This family member is distributed widely in the human multiple tissue, and except the release that comes off of regulating somatomedin and cytokine, ADAMs also participates in regulating various physiological processes, and as fertilization process, neural, muscle forms wound healing etc.
Multinomial studies show that, the release of ErbB family part and receptor activation process be active closely related with ADAMs all.For example, the cell of ADAM-17 disappearance can't normally discharge TGF α, HB-EGF and amphiregulin; By using inhibitors of metalloproteinase, can produce restraining effect to the epithelial breeding of Mammals by the ErbB mediation, this restraining effect is along with the adding of soluble EGF can be eliminated simultaneously, illustrate that this breeding is influenced by the degree of cell expressing EGF, and metalloprotease participates in adjusting (the Dong J. of this process, etal.Proc.Natl.Acad.Sci., USA96 (11): 6235-6240 (1999)); Simultaneously, in the process of the crosslinked activation of g protein coupled receptor EGFR signal, the important factor HB-FGE and the amphiregulin that specifically play a role, its dispose procedure also are proved by metalloprotease regulation and control (Prenzel N.et al.Nature 402:884-888 (1999)).In addition, through finding with clinical study before clinical, there is action compensating between different ErbB signal paths in the tumour cell, can't suppresses tumor growth (Konecny G.E., et al.Cancer Res.66:1630-1639 (2006)) the inhibition of single signal path or target spot.Therefore by inhibition to ADAMs, especially suppress to regulate the ADAM10 and the ADAM17 that come off and discharge of most ErbB parts, suppress when can realize to regulate, and then overcome the possibility that the tolerance effect produces in the oncotherapy, improve result of treatment a plurality of signal path.
The ErbB signal path of ADAMs mediation is regulated the adjusting that is not limited only to the part dispose procedure, more can directly act on ErbB acceptor itself, especially the Her-2 acceptor.Analyze by blood tumour patient, find wherein to have the Her-2 acceptor born of the same parents ectodomain fragment of higher concentration to exist, and then infer that this may be to cause patient's poor prognosis and the low potential cause (Christianson of therapeutic response, et al.Cancer Res., 58:5123-5129 (1998); Baselga J.Clin.Cancer Res., 7:2605-2607 (2001)).By discovering, the phenomenon that Her-2 acceptor born of the same parents ectodomain comes off often appears on the cell strain of Her-2 high level expression.Simultaneously, the Her-2 acceptor p95 fragment that still is combined in after the hydrolysis on the cytolemma shows the continuous activation state.In the cell transformation test under the conditions in vitro, remaining p95 fragment even show the activity (Codony-Servat J., et a1.Cancer Res., 59:1196-1201 (1999)) that is higher than 0 times of normal Her-2 acceptor 10.For the patient with breast cancer, the segmental existence of highly active her-2 acceptor p95 is indicating high transitivity and low survival rate usually.In addition, through clinical confirmation, for the metastatic breast cancer patient of high expression level Her-2 acceptor in the process of using Herceptin (trastuzumab) treatment, high-caliber Her-2 acceptor born of the same parents ectodomain can significantly reduce the interior transformation period of body of trastuzumab in the blood, and then reduce (the Baselga J. that affects the treatment its action time, et a1.Semin.Oncol., 26:78-83 (1999)).
In addition, ADAM albumen also participates in other multiple regulating cell propagation, adheres to the signal path of the process that shifts, and detailed description can be referring to Dylan.R, et al, Molecular Aspect of Medicine, 29:258-289 (2008).
The potential treatment indication of ADAMs inhibitor is disclosed in the literature.Referring to for example U.S. Patent number 6,500,847 (Bayer Corporation), U.S. Patent number 6, (268.379 DuPont PharmaceuticalsCompany), U.S. Patent number 5,968,795 (Bayer Corporation), U.S. Patent number 5,892,112 (Glycomed Incorporated and The University of Florida) and U.S. Patent numbers 5,872,152 (British Biotech Pharmaceuticals Limited).Some examples useful to the metal proteinase activity restraining effect comprise: a) osteoarthritis, b) for example autoimmune disease, rheumatoid arthritis of rheumatism or illness, c) septicemia sacroiliitis, d) cancer comprises that tumor growth, metastases and blood vessel take place, e) periodontal disease etc.
In sum, be the selectivity inhibition compound of target spot with ADAM, can be used for treating effectively tumor disease, especially with the unusual closely-related tumor type of ErbB receptor signal path; Simultaneously by ADAMs being selected inhibitor and the medication combined application of other traditional treatments, can avoid the result of treatment that produces under the single therapy method low, reduce possibility that tumour cell produces drug resistance, especially for the treatment of the cancer for the treatment of the Her-2 high expression level.Therefore, exploitation has the compound of ADAMs selectivity inhibition to improving the clinical treatment predicament, and increasing treatment means all has significance.
Summary of the invention
In order to overcome the deficiencies in the prior art part, the object of the present invention is to provide azabicyclo-octane hydroxamic acid derivatives shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug.
Figure GSA00000049713000031
Wherein:
R 1Be selected from alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl or-NR 5R 6, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 2And R 3Independently be selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxyl group, cycloalkyl or heterocyclic radical separately, wherein said alkyl, alkoxyl group, cycloalkyl or heterocyclic radical optional further by one or more be selected from halogen, alkyl, alkoxyl group, carboxylic acid, carboxylicesters or-NR 5R 6Substituting group replace;
Perhaps, R 2Or R 3Can form with the carbon atom that is connected-C=O ,-C=C (R 8R 9), cycloalkyl or heterocyclic radical, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described cycloalkyl or heterocyclic radical are optional is further replaced by one or more substituting groups that are selected from halogen, hydroxyl, nitro, cyano group or alkyl;
R 4Be selected from hydrogen atom, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical ,-C (O) NR 5R 6,-S (O) 2NR 5R 6,-C (O) OR 7Or-C (O) R 7, wherein said alkyl, alkoxyl group, cycloalkyl or heterocyclic radical optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters ,-NR 5R 6Or-OR 7Substituting group replace;
R 5And R 6Independently be selected from hydrogen atom, halogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further by one or more R aSubstituting group replaces;
Perhaps, R 5And R 6Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical is optional further by one or more R aSubstituting group replaces;
R 7Be selected from hydrogen atom, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from hydroxyl, halogen, nitro, cyano group, alkyl, alkoxyl group, heterocyclic radical, aryl, heteroaryl, carboxylic acid, carboxylicesters or-NR 5R 6Substituting group replace;
R 8And R 9Independently be selected from hydrogen atom, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, carboxylic acid or carboxylicesters separately, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl or heterocyclic radical optional further by one or more be selected from halogen, nitro, cyano group, alkyl, alkoxyl group, heterocyclic radical, aryl, heteroaryl, carboxylic acid, carboxylicesters or-NR 5R 6Substituting group replace;
R aBe selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-C (O) OR 7,-OC (O) R 7,-O (CH 2) qC (O) OR 7,-S (O) pR 7,-C (O) R 7,-OS (O) OR 7,-NHC (O) R 7,-NR 10R 11,-OC (O) NR 10R 11Or-S (O) ONR 10R 11, wherein alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-C (O) OR 7,-OC (O) R 7,-O (CH 2) qC (O) OR 7,-S (O) pR 7,-C (O) R 7,-OS (O) OR 7,-NHC (O) R 7,-NR 10R 11,-OC (O) NR 10R 11Or-S (O) ONR 10R 11Substituting group replace;
R 10And R 11Independently be selected from hydrogen atom, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further by one or more R bSubstituting group replaces;
Perhaps, R 10And R 11Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical is optional further by one or more R bSubstituting group replaces;
R bBe selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 10R 11,-OC (O) NR 10R 11,-S (O) ONR 10R 11,-C (O) R 7,-C (O) OR 7,-OC (O) R 7,-O (CH 2) qC (O) OR 7,-S (O) pR 7,-OS (O) OR 7Or-NHC (O) R 7, wherein alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 7,-C (O) OR 7,-OC (O) R 7,-O (CH 2) qC (O) OR 7,-S (O) pR 7,-OS (O) OR 7Or-NHC (O) R 7Substituting group replace;
R 12And R 13Independently be selected from hydrogen atom, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately;
M is 1 or 2;
N is 0 or 1;
P is 0,1 or 2; And
Q is 0,1 or 2.
Preferred compound of the present invention is the compound shown in the general formula (II) or its pharmaceutically useful salt:
Figure GSA00000049713000051
Wherein:
R 1～R 4, m, n definition such as general formula (I) described in.
Preferred compound of the present invention is the compound shown in the general formula (III) or its pharmaceutically useful salt:
Figure GSA00000049713000052
Wherein:
R 1～R 4, m, n definition such as general formula (I) described in.
Preferred compound of the present invention is the compound shown in the general formula (IV) or its pharmaceutically useful salt:
Figure GSA00000049713000061
Wherein:
R 1～R 4, m, n definition such as general formula (I) described in.
Preferred compound of the present invention or its pharmaceutically useful salt, wherein R 2And R 3Be selected from hydrogen atom.
Preferred compound of the present invention or its pharmaceutically useful salt, wherein R 4Be selected from-C (O) NR 5R 6Or-C (O) OR 10
Preferred compound of the present invention or its pharmaceutically useful salt, wherein R 5And R 6Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical is optional further by one or more R aSubstituting group replaces.
Therefore general formula (I) compound can contain unsymmetrical carbon, can exist or exist as the mesomeride compound with the form of the mixture of optically pure diastereomer, non-enantiomer mixture, diastereomer racemic modification, non-mapping racemic modification.The present invention includes all these forms.The mixture of non-enantiomer mixture, non-mapping racemic modification or non-mapping racemic modification can pass through ordinary method, for example waits with HPLC by column chromatography, tlc and separates.
Typical compound of the present invention includes, but are not limited to:
Figure GSA00000049713000071
Figure GSA00000049713000091
Or its pharmaceutically useful salt.
The present invention relates to the synthetic method of a kind of preparation general formula (I) compound or its pharmaceutically useful salt, this method comprises general formula (IA) compound
Figure GSA00000049713000092
Optionally hydrolyse becomes carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (I) compound;
Wherein:
M, n, R 1～R 4Definition such as general formula (I) described in,
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace; R 7Definition such as general formula (I) described in.
The present invention relates to the synthetic method of a kind of preparation general formula (II) compound or its pharmaceutically useful salt, this method comprises general formula (IIA) compound,
Figure GSA00000049713000093
Optional its is hydrolyzed into carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (II) compound;
Wherein:
M, n, R 1～R 4Definition such as general formula (II) described in,
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as general formula (II) described in.
The present invention relates to the synthetic method of a kind of preparation general formula (III) compound or its pharmaceutically useful salt, this method comprises compound a
Figure GSA00000049713000101
With formula (CHR 2R 3) m-PG 2Reaction obtains product b;
Then optional with product b
Figure GSA00000049713000102
Through thio reaction, further be converted into sulfuryl c;
And then with product c
Figure GSA00000049713000103
The optional reaction under alkaline condition with formula R-H obtains product general formula (IIIA);
Then with product general formula (IIIA)
Figure GSA00000049713000104
Optionally hydrolyse becomes carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (III) compound;
Wherein:
M, G, R 1～R 4Definition such as general formula (III) described in; PG is selected from leavings group, is preferably I, Br, Cl or methylsulfonyl; G ' is selected from halogen, hydroxyl or alkyl.
The present invention relates to the synthetic method of a kind of preparation general formula (III) compound or its pharmaceutically useful salt, this method comprises compound b
Figure GSA00000049713000111
Obtain product d with formula R-SH reaction;
Then with product d
Figure GSA00000049713000112
Choose that general-S-is converted into sulfuryl e under suitable condition wantonly;
Then with product e
Figure GSA00000049713000113
Optionally hydrolyse becomes carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (III) compound;
Wherein:
M, G, R 1～R 4Definition such as general formula (III) described in; PG is selected from leavings group, is preferably I, Br, Cl or methylsulfonyl.
Further, the present invention relates to the compound shown in a kind of general formula (IA) or its pharmaceutically useful salt, it is as the intermediate of preparation general formula (I) compound or its pharmaceutically useful salt:
Wherein:
M, n, R 1～R 4Definition such as general formula (I) described in;
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as general formula (I) described in.
The present invention relates to the described compound of a kind of general formula (IIA) or its pharmaceutically useful salt, it is as the intermediate of preparation general formula (II) compound or pharmaceutically acceptable salt thereof:
Figure GSA00000049713000122
Wherein:
M, n, R 1～R 4Definition such as general formula (II) described in;
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as general formula (II) described in.
The present invention relates to the described compound of a kind of general formula (IIIA) or its pharmaceutically useful salt, it is as the intermediate of preparation general formula (III) compound or pharmaceutically acceptable salt thereof:
Wherein:
M, R 1～R 4Definition such as general formula (III) described in;
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as general formula (III) described in.
The preferred compound of general formula (IA) includes, but are not limited to:
Figure GSA00000049713000131
Figure GSA00000049713000141
Figure GSA00000049713000161
Figure GSA00000049713000171
Figure GSA00000049713000181
Figure GSA00000049713000191
Figure GSA00000049713000201
Figure GSA00000049713000211
Figure GSA00000049713000221
Or its pharmaceutically useful salt.
Further, the present invention relates to the compound shown in a kind of general formula a or its pharmaceutically useful salt:
Figure GSA00000049713000222
Wherein:
R 4Definition such as general formula (III) described in;
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as general formula (III) described in.
The typical compound of general formula a compound or its pharmaceutically useful salt includes, but are not limited to:
Or its pharmaceutically useful salt.
Another aspect of the present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, the purposes in preparation metalloprotein kinase inhibitor, and wherein said metalloprotein kinases is selected from ADAM10.
Another aspect of the present invention relates to the kinase whose method of a kind of inhibition metalloprotein, and this method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, and wherein said metalloprotein kinases is selected from ADAM10.
Another aspect of the present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt as suppressing the kinase whose medicine of metalloprotein, and wherein said metalloprotein kinases is selected from ADAM10.
Another aspect of the present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt, the purposes in the medicine of preparation treatment cancer, and wherein said cancer is lung cancer, mammary cancer, epidermis squama cancer or cancer of the stomach.
Another aspect of the present invention relates to a kind of treatment method for cancer, and this method comprises general formula (I) compound or its pharmaceutically useful salt of the effective therapeutic dose of patient that needs treatment, and wherein said cancer is lung cancer, mammary cancer, epidermis squama cancer or cancer of the stomach.
Another aspect of the present invention relates to general formula of the present invention (I) compound or its pharmaceutically useful salt medicine as the treatment cancer, and wherein said cancer is lung cancer, mammary cancer, epidermis squama cancer or cancer of the stomach.
Further, another aspect of the present invention relates to a kind of pharmaceutical composition, and it contains The compounds of this invention or its pharmacy acceptable salt for the treatment of effective dose, and pharmaceutically useful carrier or vehicle.The purposes of this pharmaceutical composition in the medicine of preparation metalloprotein kinase inhibitor.This pharmaceutical composition in the medicine of the preparation treatment disease relevant with the metalloprotein kinases purposes, wherein said metalloprotein kinases is selected from ADAM-10.The purposes of said composition in the medicine of preparation treatment cancer, wherein said cancer is lung cancer, mammary cancer, epidermis squama cancer or cancer of the stomach.
Another aspect of the present invention relates to the kinase whose method of a kind of inhibition metalloprotein, this method comprises needs the patient of treatment to contain general formula (I) compound of effective therapeutic dose or the pharmaceutical composition of its pharmaceutically useful salt, and wherein said metalloprotein kinases is selected from ADAM10.
Another aspect of the present invention relates to the pharmaceutical composition that contains general formula of the present invention (I) compound or its pharmaceutically useful salt as suppressing the kinase whose medicine of metalloprotein, and wherein said metalloprotein kinases is selected from ADAM10.
Another aspect of the present invention relates to a kind of treatment method for cancer, this method comprises needs the patient of treatment to contain general formula (I) compound of effective therapeutic dose or the pharmaceutical composition of its pharmaceutically useful salt, and wherein said cancer is lung cancer, mammary cancer, epidermis squama cancer or cancer of the stomach.
Another aspect of the present invention relates to the pharmaceutical composition that contains general formula of the present invention (I) compound or its pharmaceutically useful salt medicine as the treatment cancer, and wherein said cancer is lung cancer, mammary cancer, epidermis squama cancer or cancer of the stomach.
Detailed description of the invention
Unless the phase counter-statement is arranged, 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, when being substituted, substituting group is preferably one or more following groups, be independently selected from alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carbonyl, halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 11,-C (O) OR 10,-OC (O) R 10,-O (CH 2) qC (O) OR 10,-S (O) pR 10,-OS (O) OR 10Or-NHC (O) R 10
" cycloalkyl " refers to the non-aromatic monocycle or encircles the ring-type system more, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 10 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 8 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexadienyl, suberane base, cycloheptatriene base etc.The polycyclic naphthene base comprises volution, condensed ring and endocyclic cycloalkyl, and non-limiting example comprises 1-naphthalane base, norcamphyl, adamantyl and similar group.Cycloalkyl 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, heterocyclic radical, aryl, heteroaryl, carbonyl, halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 11,-C (O) OR 10,-OC (O) R 10,-O (CH 2) qC (O) OR 10,-S (O) pR 10,-OS (O) OR 10Or-NHC (O) R 10
" thiazolinyl " refers to the alkyl as defined above be made up of at least two carbon atoms and at least one carbon-to-carbon double bond.For example vinyl, 1-propenyl, 2-propenyl, 1-, 2-or 3-butenyl etc.Thiazolinyl 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, heterocyclic radical, aryl, heteroaryl, carbonyl, halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 11,-C (O) OR 10,-OC (O) R 10,-O (CH 2) qC (O) OR 10,-S (O) pR 10,-OS (O) OR 10Or-NHC (O) R 10
" alkynyl " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond are formed.For example ethynyl, 1-proyl, 2-propynyl, 1-, 2-or 3-butynyl etc.Alkynyl 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, heterocyclic radical, aryl, heteroaryl, carbonyl, halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 11,-C (O) OR 10,-OC (O) R 10,-O (CH 2) qC (O) OR 10,-S (O) pR 10,-OS (O) OR 10Or-NHC (O) R 10
" heterocyclic radical " refers to the monocycle of non-aromatic or encircles the ring-type system more, it comprises 3 to 20 annular atomses, wherein one or more annular atomses are selected from the heteroatoms of nitrogen, oxygen or S (O) n (wherein n is an integer 0 to 2), but do not comprise-O-O-,-O-S-or-loop section of S-S-, all the other annular atomses are carbon.Preferred heterocyclic radical comprises 3～10 annular atomses, and wherein 1～4 is heteroatoms, and more preferably heterocyclic radical comprises 3～8 annular atomses.The non-limiting example of monocyclic heterocycles base comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, high piperazinyl etc., encircles heterocyclic radical more and comprises dicyclo or polycyclic volution, condensed ring and endocyclic heterocyclic radical.Heterocyclic radical 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, heterocyclic radical, aryl, heteroaryl, carbonyl, halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 11,-C (O) OR 10,-OC (O) R 10,-O (CH 2) qC (O) OR 10,-S (O) pR 10,-OS (O) OR 10Or-NHC (O) R 10
" 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 has phase adjacency pair carbon atom) group with conjugated πDian Zi system, be preferably 6 to 10 yuan, for example phenyl, naphthyl and anthryl.Aryl 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, heterocyclic radical, aryl, heteroaryl, carbonyl, halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 11,-C (O) OR 10,-OC (O) R 10,-O (CH 2) qC (O) OR 10,-S (O) pR 10,-OS (O) OR 10Or-NHC (O) R 10
" 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 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, 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, heterocyclic radical, aryl, heteroaryl, carbonyl, halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 11,-C (O) OR 10,-OC (O) R 10,-O (CH 2) qC (O) OR 10,-S (O) pR 10,-OS (O) OR 10Or-NHC (O) R 10
" aralkyl " comprises the alkyl that finger is replaced by aryl, and preferred aralkyl is to have the rudimentary aralkyl of the aryl that is connected with the alkyl that contains 1～6 carbon atom, more preferably is connected to " phenyl alkylidene group " on the moieties with 1～3 carbon atom.For example, benzyl, 1-styroyl, 2-styroyl, 1-naphthyl methyl, 2-naphthyl methyl are preferably benzyl.Aryl in the described aralkyl can be that replace or unsubstituted, when being substituted, substituting group be preferably alkyl, alkoxyl group, halogen, hydroxyl, nitro, cyano group, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carbonyl, halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 11,-C (O) OR 10,-OC (O) R 10,-O (CH 2) qC (O) OR 10,-S (O) pR 10,-OS (O) OR 10Or-NHC (O) R 10
" 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, is independently selected to be halogen, alkoxyl group, hydroxyl, amino, cyano group, nitro, cycloalkyl or heterocyclic radical.
" 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
" 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 " expression contains on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components physiology/pharmaceutically useful carrier and vehicle for example.The purpose of pharmaceutical composition is the administration that promotes organism, is beneficial to the absorption and then the performance biological activity of activeconstituents.
M, n, q, p and R 7～R 13Definition such as general formula (I) compound 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 a kind of general formula (I) compound, this method comprises:
Figure GSA00000049713000261
Compound (IA) optionally hydrolyse becomes carboxylic acid and azanol or hydroxylammonium salt reaction, obtains general formula (I) compound;
Wherein:
G is selected from hydrogen atom or alkyl;
M, n, R and R 1～R 4Definition such as general formula (I) described in.
The preparation method of a kind of general formula (II) compound, this method comprises:
Figure GSA00000049713000262
Compound (IA) optionally hydrolyse becomes carboxylic acid and azanol or hydroxylammonium salt reaction, obtains general formula (II) compound;
Wherein:
G is selected from hydrogen atom or alkyl;
M, n, R and R 1～R 4Definition such as general formula (II) described in.
The synthetic method of a kind of general formula (III), this method comprises:
Figure GSA00000049713000271
Compound a and formula (CHR 2R 3) m-PG 2Reaction is then chosen wantonly product b process thio reaction, further is converted into sulfuryl, and the product c and the formula R-H that obtain react under alkaline condition, obtain general formula (IIIA) product; General formula (IIIA) compound optionally hydrolyse becomes carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (III) compound; Wherein:
G is selected from hydrogen atom or alkyl;
G ' is selected from halogen, hydroxyl or alkyl;
PG is selected from leavings group, is preferably I, Br, Cl or methylsulfonyl;
M, R and R 1～R 3Definition such as general formula (III) described in.
The synthetic method of a kind of general formula (III), this method comprises:
Figure GSA00000049713000272
Compound b and formula R-SH reaction, the product d that obtains general-S-under suitable condition is converted into sulfuryl and obtains general formula (IIIA) product; General formula (IIIA) product optionally hydrolyse reacts with azanol or hydroxylammonium salt after becoming carboxylic acid, obtains general formula (III) compound;
Wherein:
G is selected from hydrogen atom or alkyl;
PG is selected from leavings group, is preferably I, Br, Cl or methylsulfonyl;
M, R and R 1～R 3Definition such as general formula (III) described in.
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 by nucleus magnetic resonance (NMR) or/and mass spectrum (MS) come to determine.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 deuterochloroform (CDCl 3), 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: Thermo, model: FinniganLCQ advantage MAX).
The mensuration of HPLC is used Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 * 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18150 * 4.6mm chromatographic column).
Kinases 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 TLC 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, Aldrich Chemical Company, reaches company such as auspicious chemical at splendid chemistry science and technology far away (AccelaChemBio Inc), 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.
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 20 ℃～30 ℃.
Tlc (TLC) is adopted in the monitoring of the reaction process among the embodiment, the system of reacting employed developping agent has: 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, C: methylene dichloride and acetone 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.
Embodiment 1
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino first Acyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids (2-morpholine ethyl) ester
Figure GSA00000049713000291
The first step
The acrylic-amino methyl-formiate
Under the ice bath, (73g 0.53mol) is dissolved in the 250mL acetonitrile, and (15g is 0.26mol) with 50mL methyl-chloroformate (30g, acetonitrile solution 0.32mol), stirring at room reaction 12 hours to drip allyl amine 1a with Anhydrous potassium carbonate.Filter, filtrate decompression concentrates, resistates 250mL acetic acid ethyl dissolution, anhydrous sodium sulfate drying is used in water (50mL * 3) and saturated nacl aqueous solution washing (50mL * 3) successively, filters, filtrate decompression concentrates, obtain title product acrylic-amino methyl-formiate 1b (26g, yellow liquid), productive rate: 86.9%.
MS?m/z(ESI)：116.1[M+1]
Second step
4-(4-chloro-2-aminomethyl phenyl)-4-hydroxy piperidine-1-carboxylic acid tert-butyl ester
(3.05g, (4g in tetrahydrofuran solution 25mmol), adds 3 of iodine, and hair dryer is heated to the iodine color and disappears 0.13mmol) to add 20mL 1-bromo-4-chloro-2-toluene 1c with magnesium rod.70 ℃ drip 80mL 1-bromo-4-chloro-2-toluene (16.6g down, tetrahydrofuran solution 75mmol), reflux 1 hour, reaction solution is cooled to 0 ℃, drip 20mL 4-oxo-piperidines-1-carboxylic acid tert-butyl ester (10g, tetrahydrofuran solution 50mmol) reacted 1 hour, and room temperature continues to stir 1 hour.Ice-water bath adds the 100mL saturated ammonium chloride solution down, and through diatomite filtration, organic phase is told in ethyl acetate washing (200mL), water ethyl acetate extraction (50mL * 3).Merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, resistates obtains title product 4-(4-chloro-2-aminomethyl phenyl)-4-hydroxy piperidine-1-carboxylic acid tert-butyl ester 1d (10.3g, white solid), productive rate: 63.38% with ethyl acetate-normal hexane recrystallization.
MS?m/z(ESI)：226.2[M-100+1]
The 3rd step
4-(4-chloro-2-aminomethyl phenyl)-1,2,3, the 6-tetrahydropyridine
Under the ice bath, (10.63g 32.7mmol) is dissolved in the 100mL methylene dichloride, and (60mL, 714mmol), stirring at room was reacted 12 hours to drip trifluoroacetic acid with 4-(4-chloro-2-aminomethyl phenyl)-4-hydroxy piperidine-1-carboxylic acid tert-butyl ester 1d.With the reaction solution concentrating under reduced pressure, add the 100mL methylene dichloride in the resistates, dripping 2M sodium hydroxide solution adjusting pH value is 11～12, tell organic phase, water merges organic phase with dichloromethane extraction (80mL * 3), with saturated nacl aqueous solution washing (80mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 4-(4-chloro-2-aminomethyl phenyl)-1,2,3,6-tetrahydropyridine 1e crude product (6.108g, brown oil), productive rate: 90.22%.
The 4th step
4-(4-chloro-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
Under the ice bath, with 4-(4-chloro-2-aminomethyl phenyl)-1,2,3, (6.1g 29.45mmol) is dissolved in the 120mL methylene dichloride 6-tetrahydropyridine 1e, adds N, N-diisopropylethylamine (9.5g, 73.6mmol), the dropping tert-Butyl dicarbonate (9.6g, 44.2mmol), stirring reaction 0.5 hour, room temperature continue to stir 1 hour.In reaction solution, add the 80mL saturated ammonium chloride solution, regulate the pH value and be about 7, with dichloromethane extraction (80mL * 3) reaction solution, merge organic phase, with saturated nacl aqueous solution washing (60mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product 4-(4-chloro-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester 1f (9g with silica gel column chromatography, white solid), productive rate: 99%.
The 5th step
4-(4-chloro-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester
With 4-(4-chloro-2-aminomethyl phenyl)-5, (6.1g 29.45mmol) is dissolved in the 100mL methyl alcohol 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester 1f, adds palladium/carbon (600mg, 10%) in reaction solution, hydrogen exchange three times, stirring reaction 12 hours.Reaction solution is through diatomite filtration, and filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 4-(4-chloro-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester 1g (9g, colorless oil), productive rate: 97.36% with silica gel column chromatography.
MS?m/z(ESI)：210.4[M-100+1]
The 6th step
4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester
With zinc cyanide (2.1g, 18mmol) and zinc (1.2g, 18mmol) add 90mL 4-(4-chloro-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester 1g (2.8g, in dimethylacetamide solution 9mmol), add two (tri-butyl phosphine) palladium (460mg, 0.9mmol), 140 ℃ of following stirring reactions 12 hours.Under 0 ℃, in reaction solution, add 10% ammoniacal liquor,, merge organic phase with ethyl acetate extraction (100mL * 3), with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester 1h (1.44g, colorless oil), productive rate: 53.3%.
MS?m/z(ESI)：201.5[M-100+1]
The 7th step
3-methyl-4-(piperidin-4-yl) benzonitrile
With 4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-carboxylic acid tert-butyl ester 1h (870mg 2.9mmol) is dissolved in 1 of 6mL 1M hydrogenchloride, in the 4-dioxane solution, stirring reaction 12 hours.The reaction solution concentrating under reduced pressure, add 10mL methylene dichloride and 10mL saturated sodium bicarbonate solution in the resistates, with dichloromethane extraction (40mL * 3), merge organic phase, with saturated nacl aqueous solution washing (5mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product 3-methyl-4-(piperidin-4-yl) benzonitrile 1i crude product (600mg, white solid), directly drop into the next step.
MS?m/z(ESI)：210.4[M-100+1]
The 8th step
2-allyl malonic acid dimethyl ester
Under the ice bath, (8.68g 0.36mol) is dissolved in the 200mL tetrahydrofuran (THF) sodium hydride with 60%, and (36mL 0.31mol), stirred 30 minutes, and (27.2mL, 0.31mol), stirring at room was reacted 12 hours to drip allyl bromide 98 to add dimethyl malonate 1j.Under 0 ℃, add the 500mL frozen water, tell organic phase, water ethyl acetate extraction (200mL * 3), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-allyl malonic acid dimethyl ester 1k (32.09g with silica gel column chromatography, colourless liquid), productive rate: 59.39%.
The 9th step
2-allyl group-2-iodine dimethyl malonate
Under the ice bath, (15.2g 0.38mol) is dissolved in the 120mL tetrahydrofuran (THF) with 60% sodium hydride, drip 60mL 2-allyl malonic acid dimethyl ester 1k (33g, 0.19mol) tetrahydrofuran solution, stirring reaction 1 hour, centrifugal, get supernatant liquid, the dry ice bath cooling drips 60mL N-iodo succimide (33.0g, tetrahydrofuran solution 0.19mol), continue to stir 30 minutes, 0 ℃ was reacted 30 minutes.Stir down reaction solution is poured in the 300mL frozen water, with ethyl acetate extraction (200mL * 3), merge organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 2-allyl group-2-iodine dimethyl malonate 1M (41.3g with silica gel column chromatography, red oil), productive rate: 72.9%.
The tenth step
(3aR, 6aS)-tetrahydro cyclopentyl [c] pyrroles-2,5,5 (1H, 3H)-the tricarboxylic acid methyl esters
With acrylic-amino methyl-formiate 1b (15.4g, 0.13mol) and 2-allyl group-2-iodine dimethyl malonate 1M (20g, 67mmol) be dissolved in the 200mL benzene, add six normal-butyls, two tin (780mg, 1.34mmol), illumination reaction 3.5 hours (2 of 150W incandescent light) adds triethylamine (34g, 0.34mol), 80 ℃ of following back flow reaction 3.5 hours.Reaction solution is reduced to room temperature, and concentrating under reduced pressure with eluent system B purifying gained resistates, obtains title product (3aR with silica gel column chromatography, 6aS)-and tetrahydro cyclopentyl [c] pyrroles-2,5,5 (1H, 3H)-and tricarboxylic acid methyl esters 1n (16.3g, light yellow liquid), productive rate: 43%.
The 11 step
(3aR, 6aS)-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Will (3aR, 6aS)-tetrahydro cyclopentyl [c] pyrroles-2,5,5 (1H, 3H)-tricarboxylic acid methyl esters 1n (8.35g 30mmol) is dissolved in the 30mL dimethyl sulfoxide (DMSO), add lithium chloride (1.5g, 35mmol) and water (0.74mL, 41mmol), 180 ℃ were reacted 2 hours down.Add 50mL water in the room temperature downhill reaction liquid, ethyl acetate extraction (100mL * 3) reaction solution merges organic phase, with saturated nacl aqueous solution washing (100mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system B purifying gained resistates, obtain title product (3aR, 6aS)-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1o (3.764g, faint yellow oily thing), productive rate: 56.6%.
MS?m/z(ESI)：228.2[M+1]
The 12 step
(3aR, 5S, 6aS)-5-(iodomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the dry ice bath, with (3aR, 6aS)-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1o (7.5g, 33mmol) be dissolved in the 150mL tetrahydrofuran (THF), the tetrahydrofuran solution of adding 2M lithium diisopropyl amido (25mL, 50mmol), stirring reaction 30 minutes, add 5.3mL methylene iodide (17.7g, tetrahydrofuran solution 66mmol) continues to stir 1 hour, and-20 ℃ were stirred 2 hours down.In reaction solution, add the 150mL saturated ammonium chloride solution,, merge organic phase with ethyl acetate extraction (100mL * 3) reaction solution, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product (3aR, 5S with silica gel column chromatography, 6aS)-5-(iodomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1p (7.5g, red-brown oily matter), productive rate: 61.9%.
The 13 step
(3aR, 5S, 6aS)-5-(acetyl thio methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Will (3aR, 5S, 6aS)-5-(iodomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1p (7.5g 20mmol) is dissolved in the 50mL tetrahydrofuran (THF), and adding acetate sulphur potassium ester (3.4g, 30mmol), stirring reaction 12 hours.Reaction solution is poured in the 200mL frozen water,, merged organic phase with ethyl acetate extraction (75mL * 3) reaction solution, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product (3aR, 5S with silica gel column chromatography, 6aS)-5-(acetyl thio methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1q (6.4g, faint yellow solid), productive rate: 99.9%.
MS?m/z(ESI)：316.2[M+1]
The 14 step
(3aR, 5S, 6aS)-5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the ice bath, with chlorosuccinimide (1.7g, 12.7mmol) be dissolved in the acetonitrile solution of 5.1mL 2M hydrochloric acid, adding 8.0mL (3aR, 5S, 6aS)-5-(acetyl thio methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1q (1g, 3.2mmol) acetonitrile solution, stirring reaction 10 minutes, 15 ℃ are continued down to stir 20 minutes.In reaction solution, add the 100mL isopropyl ether, with saturated nacl aqueous solution washing (50mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (3aR, 5S, 6aS)-5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1r crude product (1.4g, colorless oil).
The 15 step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the ice bath, (600mg 3mmol) is dissolved in the 15mL methylene dichloride, adds N successively with 3-methyl-4-(piperidin-4-yl) benzonitrile 1i, N-diisopropylethylamine (770g, 6mmol) and 15mL (3aR, 5S, 6aS)-5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1r (1.4g, dichloromethane solution 3mmol), stirring reaction 30 minutes continues under the room temperature to stir 1 hour.In reaction solution, add the 100mL methylene dichloride; use saturated ammonium chloride solution (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 1s (750mg, white solid), productive rate: 49.6%.
MS?m/z(ESI)：504.4[M+1]
The 16 step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under 50 ℃; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; (750mg 1.50mmol) is dissolved in the 20mL methylene dichloride 5 (1H)-dicarboxylic acid methyl esters 1s, adds Iodotrimethylsilane (900mg; 4.50mmol), stirring reaction 4 hours.Under the ice bath, in reaction solution, add 2mL methyl alcohol, 10mL water and 50mL saturated sodium bicarbonate solution; with dichloromethane extraction (50mL * 3); merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and obtains title product (3aR, 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1t crude product (720mg, faint yellow solid).
The 17 step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1t (720mg; 1.50mmol) be dissolved in the 20mL methylene dichloride; add N; the N-carbonyl dimidazoles (486mg, 3mmol), stirring reaction 12 hours.In reaction solution, add the 100mL methylene dichloride; water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1u (740mg; white solid), productive rate: 91.4%.
The 18 step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-5-carboxylate methyl ester-2-carboxylic acid (2-morpholine ethyl) ester
Under the ice bath; with 2-morpholine ethanol (67mg; 0.51mmol) be dissolved in the 12mL tetrahydrofuran (THF), the sodium hydride of adding 60% (41mg, 1mmol); stirring reaction 5 minutes; add (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1u (250mg; 0.46mmol), continue to stir 40 minutes.Reaction solution is poured in the 50mL frozen water; with dichloromethane extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5S with silica gel column chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-5-carboxylate methyl ester-2-carboxylic acids (2-morpholine ethyl) ester 1v (138mg, white solid), productive rate: 49.8%.
MS?m/z(ESI)：603.3[M+1]
The 19 step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-((2-morpholine oxyethyl group) carbonyl) octahydro ring penta [c] tetramethyleneimine-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-5-carboxylate methyl ester-2-carboxylic acids (2-morpholine ethyl) ester 1v (132mg; 0.22mmol) be dissolved in 1.5mL tetrahydrofuran (THF) and the 1.5mL methyl alcohol; add lithium hydroxide (41mg, 1mmol) and water (0.3mL), stirring reaction 12 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with 1M hydrochloric acid; with dichloromethane extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-((2-morpholine oxyethyl group) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 1w crude product (145mg; white solid), product directly carries out next step reaction without separating.
The 20 step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids (2-morpholine ethyl) ester
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-((2-morpholine oxyethyl group) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 1w (140mg; 0.22mmol) be dissolved in 2mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (146mg; 0.33mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (140mg; 2mmol) and N-methylmorpholine (111mg; 1.10mmol), stirring reaction 1 hour continues under the room temperature to stir 3 hours.Reaction solution is poured in the 20mL frozen water; with dichloromethane extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids (2-morpholine ethyl) ester 1 (60mg; white solid), productive rate: 45.2%.
MS?m/z(ESI)：604.5[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.517(d，2H，J＝7.6Hz)，7.322(s，1H)，3.98(d，2H，J＝11.2Hz)，3.763(m，4H)，3.472(m，6H)，3.043(m，8H)，2.787(m，4H)，2.395(s，3H)，2.069(m，2H)，1.873(m，4H)
Embodiment 2
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino first Acyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid (S)-pyrroles-2-methyl esters
Figure GSA00000049713000351
The first step
(S)-2-(methylol) tetramethyleneimine-1-benzyl carboxylate
Under the ice bath, with (S)-tetramethyleneimine-2-base methyl alcohol 2a (3g 30mmol) is dissolved in the 60mL methylene dichloride, add triethylamine (4g, 39mmol) and chloroformic acid benzyl ester (6.2g, 36mmol), stirring reaction 1 hour, room temperature continues stirring 12 hours.Under the ice bath reaction solution is poured in the 200mL saturated ammonium chloride solution, with dichloromethane extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product (S)-2-(methylol) tetramethyleneimine-1-benzyl carboxylate 2b (7.12g with silica gel column chromatography, yellow oil), productive rate: 99.9%.
MS?m/z(ESI)：102.5[M-100+1]
Second step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester
Under the ice bath; with (S)-2-(methylol) tetramethyleneimine-1-benzyl carboxylate 2b (140mg; 0.60mmol) be dissolved in the 12mL tetrahydrofuran (THF); add 60% sodium hydride (46mg successively; 1.10mmol) and (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1u (290mg; 0.54mmol), stirring reaction 40 minutes.Reaction solution is poured in the 30mL frozen water; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5R with silica gel column chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 2c (130mg, white solid), productive rate: 34.1%.
The 3rd step
(3aR, 5R, 6aS)-2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 2c (130mg; 0.18mmol) be dissolved in 1.5mL tetrahydrofuran (THF) and the 1.5mL methyl alcohol; add lithium hydroxide (77mg, 1.84mmol) and water (0.3mL), stirring reaction 12 hours.Reaction solution is poured in the frozen water (30mL); regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 2d (104mg, white solid), productive rate: 83.4%.
The 4th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters
Under the ice bath; with (3aR; 5R; 6aS)-2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 2d (104mg; 0.15mmol) be dissolved in 2mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (100mg; 0.23mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (32mg; 0.46mmol) and N-methylmorpholine (76mg; 0.75mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters 2e (80mg, white solid), productive rate: 75.3%.
MS?m/z(ESI)：708.5[M+1]
The 5th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid (S)-tetramethyleneimine-2-methyl esters
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters 2e (45mg; 0.064mmol) be dissolved in 4mL tetrahydrofuran (THF) and water (V: V=1: in the mixed solvent 1); add trifluoroacetic acid (11mg successively; 0.096mmol) and 5% palladium barium sulfate (27mg), hydrogen exchange three times, stirring reaction 4 hours.Filter; filtrate is separated with the HPLC preparation; obtain title product (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid (S)-tetramethyleneimine-2-methyl esters 2 (20mg; white solid), productive rate: 37.9%.
MS?m/z(ESI)：574.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.471(m，2H)，7.303(s，1H)，3.876(d，2H，J＝10.8Hz)，3.689(m，2H)，3.593(m，2H)，3.525(m，2H)，3.319(m，4H)，2.300(m，1H)，3.100(m，1H)，3.000(m，1H)，2.839(m，4H)，2.353(m，1H)，2.293(s，3H)，2.271(m，1H)，2.022(m，1H)，1.915(m，8H)
Embodiment 3
(3aR, 5R, 6aS)-(5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) Six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester
Figure GSA00000049713000381
The first step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester
Under the ice bath; with (S)-3-hydroxyl tetrahydrofuran (46mg; 0.52mmol) be dissolved in the 12mL tetrahydrofuran (THF); add 60% sodium hydride (41mg successively; 1mmol) and (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1u (240mg; 0.45mmol), stirring reaction 30 minutes.Reaction solution is poured in the 30mL frozen water; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5R with silica gel column chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester 3a (120mg, white solid), productive rate: 47.6%.
MS?m/z(ESI)：560.4[M+1]
Second step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester 3a (120mg; 0.21mmol) be dissolved in 1.5mL tetrahydrofuran (THF) and the 1.5mL methyl alcohol; add lithium hydroxide (88mg, 2.10mmol) and water (0.3mL), stirring reaction 12 hours.Reaction solution is poured in the 30mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; obtain title product (3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 3b (110mg; white solid) crude product, productive rate: 96.0%.
The 3rd step
(3aR, 5R, 6aS)-(5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester
Under the ice bath; with (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 3b (110mg; 0.20mmol) be dissolved in 2mLN; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (133mg; 0.30mmol), stirring reaction 30 minutes adds oxammonium hydrochloride (42mg; 0.60mmol) and N-methylmorpholine (101mg; 1mmol), continue to stir 1 hour stirring at room reaction 3 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-(5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) esters 3 (45mg, white solid), productive rate: 40%.
MS?m/z(ESI)：561.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.534(m，2H)，7.328(s，1H)，5.288(s，1H)，4.007(m，4H)，3.680(m，4H)，3.408(m，2H)，2.888(m，4H)，2.456(m，1H)，2.406(s，3H)，2.206(m，1H)，2.191(m，1H)，1.893(m，4H)，1.807(m，2H)，1.718(m，4H)
Embodiment 4
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six Hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid (S)-tetramethyleneimine-2-base methyl esters
Figure GSA00000049713000391
Figure GSA00000049713000401
The first step
4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-carboxylic acid tert-butyl ester
With piperazine-1-carboxylic acid tert-butyl ester 4a (2.23g, 12mmol) with 4-bromo-3-methylbenzene acetonitrile (1.95g, 10mmol) be dissolved in the 15mL toluene, the adding acid chloride (112mg, 0.50mmol), 1,1 '-two (diphenylphosphine) ferrocene (554mg, 1mmol) and sodium tert-butoxide (1.4g, 14mmol), 90 ℃ of following stirring reactions 5 hours.Through diatomite filtration, filtrate decompression concentrates, and with eluent system B purifying gained resistates, obtains title product 4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-carboxylic acid tert-butyl ester 4b (656mg, faint yellow solid), productive rate: 21% with silica gel column chromatography.
Second step
3-methyl-4-(piperazine-1-yl) benzonitrile
With 4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-carboxylic acid tert-butyl ester 4b (1.1g 4.08mmol) is dissolved in 1 of 25mL 1M hydrogenchloride, in the 4-dioxane solution, stirring reaction 12 hours.Add 20mL methylene dichloride and 20mL saturated sodium bicarbonate solution behind the reaction solution concentrating under reduced pressure, stir after 10 minutes with dichloromethane extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product 3-methyl-4-(piperazine-1-yl) benzonitrile 4c crude product (853mg, brown solid), directly drop into the next step.
MS?m/z(ESI)：202.3[M+1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the ice bath, (450mg 2.20mmol) is dissolved in the 10mL methylene dichloride, adds N with 3-methyl-4-(piperazine-1-yl) benzonitrile 4c, N-diisopropylethylamine (620mg, 4.80mmol) and 10mL (3aR, 5S, 6aS)-5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1r (0.9g, 2.40mmol) dichloromethane solution, stirring reaction 30 minutes, room temperature reaction 12 hours.In reaction solution, add the 100mL methylene dichloride; use saturated ammonium chloride solution (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 4d (643mg, faint yellow solid), productive rate: 57.9%.
MS?m/z(ESI)：505.3[M+1]
The 4th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 4d (610mg; 1.20mmol) be dissolved in the 15mL methylene dichloride; add Iodotrimethylsilane (726mg, 3.60mmol), 50 ℃ of following stirring reactions 4 hours.The reaction solution ice bath is cooled to 0 ℃, adds 2mL methyl alcohol, 10mL water and 30mL saturated sodium bicarbonate solution; with dichloromethane extraction (40mL * 3); merge organic phase, with saturated nacl aqueous solution washing (30mL * 2), anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and obtains title product (3aR, 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 4e crude product (800mg, faint yellow solid).
The 5th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 4e (800mg; 1.20mmol) be dissolved in the 15mL methylene dichloride; add N; the N-carbonyl dimidazoles (390mg, 2.40mmol), stirring reaction 12 hours.In reaction solution, add the 100mL methylene dichloride; water (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 4f (550mg; faint yellow solid), productive rate: 84.8%.
The 6th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester
Under the ice bath; with (S)-2-(methylol) tetramethyleneimine-1-benzyl carboxylate 2b (218mg; 0.92mmol) be dissolved in the 10mL tetrahydrofuran (THF), the sodium hydride of adding 60% (55mg, 1.38mmol); stirring reaction 5 minutes; add (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 4f (250mg; 0.46mmol), continue to stir 40 minutes.Reaction solution is poured in the 50mL frozen water; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5R with silica gel column chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 4g (100mg, white solid), productive rate: 30.7%.
MS?m/z(ESI)：708.5[M+1]
The 7th step
(3aR, 5R, 6aS)-2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 4g (100mg; 0.14mmol) be dissolved in 2mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (59mg, 1.40mmol) and water (0.2mL), stirring reaction 12 hours.Reaction solution is poured in the 40mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 4h (75mg, white solid), productive rate: 77.2%.
MS?m/z(ESI)：694.5[M+1]
The 8th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters
Under the ice bath; with (3aR; 5R; 6aS)-2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 4h (75mg; 0.11mmol) be dissolved in 2mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (73mg; 0.17mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (23mg; 0.33mmol) and N-methylmorpholine (56mg; 0.55mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters 4i (80mg, white solid), productive rate: 99.9%.
MS?m/z(ESI)：709.5[M+1]
The 9th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid (S)-tetramethyleneimine-2-base methyl esters
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters 4i (80mg; 0.11mmol) be dissolved in 8mL tetrahydrofuran (THF) and water (V: V=1: in the mixed solvent 1); add trifluoroacetic acid (19mg; 0.17mmol) and 5% palladium barium sulfate (48mg), hydrogen exchange three times, stirring reaction 4 hours.Filter; filtrate is separated with the HPLC preparation; obtain title product (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid (S)-tetramethyleneimine-2-base methyl esters 4 (20mg; white solid), productive rate: 31.6%.
MS?m/z(ESI)：575.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.465(m，2H)，7.009(d，1H，J＝4.8Hz)，3.997(m，2H)，3.720(m，2H)，3.631(m，2H)，3.571(m，2H)，3.489(m，4H)，3.381(m，2H)，3.236(m，1H)，2.958(m，6H)，2.839(m，2H)，2.400(m，1H)，2.291(s，3H)，2.244(m，2H)，1.917(m，1H)，1.816(m，2H)
Embodiment 5
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six Hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid ((S)-tetrahydrofuran (THF)-3-yl) ester
Figure GSA00000049713000431
The first step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester
Under the ice bath; with (S)-3-hydroxyl tetrahydrofuran (65mg; 0.74mmol) be dissolved in the 10mL tetrahydrofuran (THF), the sodium hydride of adding 60% (44mg, 1.11mmol); stirring reaction 10 minutes; add (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 4f (200mg; 0.37mmol), continue to stir 30 minutes.Reaction solution is poured in the 30mL frozen water; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5R with silica gel column chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester 5a (49mg, white solid), productive rate: 23.6%.
MS?m/z(ESI)：561.4[M+1]
Second step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester 5a (90mg; 0.16mmol) be dissolved in 1.2mL tetrahydrofuran (THF) and the 1.2mL methyl alcohol; add lithium hydroxide (67mg, 1.60mmol) and water (0.24mL), stirring reaction 12 hours.Reaction solution is poured in the 30mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; obtain title product (3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 5b (85mg; white solid) crude product, productive rate: 97.2%.
MS?m/z(ESI)：547.4[M+1]
The 3rd step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester
Under the ice bath; with (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 5b (85mg; 0.16mmol) be dissolved in 2mLN; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (103mg; 0.23mmol), stirring reaction 30 minutes adds oxammonium hydrochloride (32mg; 0.46mmol) and N-methylmorpholine (79mg; 0.78mmol), continue to stir 1 hour stirring at room reaction 3 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) esters 5 (67mg, white solid), productive rate: 74.6%.
MS?m/z(ESI)：562.1[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.479(m，2H)，7.017(d，1H，J＝8Hz)，5.247(m，1H)，3.883(m，4H)，3.491(m，8H)，3.020(m，4H)，2.899(m，2H)，2.419(m，2H)，2.302(s，3H)，2.199(m，1H)，2.090(m，1H)，1.844(m，4H)
Embodiment 6
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six Hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid-(2-morpholine ethyl) ester
Figure GSA00000049713000451
The first step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids (2-morpholine ethyl) ester-5-carboxylate methyl ester
Under the ice bath; (182mg 1.40mmol) is dissolved in the 15mL tetrahydrofuran (THF), adds 60% sodium hydride (83mg with the 2-morpholine ethanol; 2.10mmol); stirring reaction 5 minutes adds (3aR, 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 4f (375mg; 0.70mmol), continue to stir 3 hours stirring at room reaction 1 hour.Reaction solution is poured in the 50mL frozen water; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5S with silica gel column chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids (2-morpholine ethyl) ester-5-carboxylate methyl ester 6a (85mg, white solid), productive rate: 20.0%.
MS?m/z(ESI)：604.4[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-((2-morpholine oxyethyl group) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids (2-morpholine ethyl) ester-5-carboxylate methyl ester 6a (85mg; 0.14mmol) be dissolved in 1mL tetrahydrofuran (THF) and the 1mL methyl alcohol; add lithium hydroxide (59mg, 1.40mmol) and water (0.2mL), stirring reaction 12 hours.Reaction solution is poured in the 20mL frozen water, regulated pH=2, with ethyl acetate extraction (30mL * 3) with 1M hydrochloric acid; merge organic phase; with saturated nacl aqueous solution washing (15mL * 2), anhydrous sodium sulfate drying, filter; filtrate decompression concentrates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-((2-morpholine oxyethyl group) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 6b crude product (80mg; white solid), productive rate 96.9%.
MS?m/z(ESI)：590.5[M+1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids-(2-morpholine ethyl) ester
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-((2-morpholine oxyethyl group) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 6b (80mg; 0.14mmol) be dissolved in 2mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (90mg; 0.20mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (28mg; 0.41mmol) and N-methylmorpholine (69mg; 0.68mmol), continue to stir 1 hour stirring at room reaction 2 hours.Reaction solution is poured in the 20mL frozen water; with dichloromethane extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids-(2-morpholine ethyl) ester 6 (45mg; white solid), productive rate: 53.2%.
MS?m/z(ESI)：605.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.415(m，2H)，7.010(d，1H，J＝8.4Hz)，4.219(m，1H)，3.794(m，4H)，3.535(m，2H)，3.388(m，8H)，3.009(m，4H)，2.860(m，4H)，2.676(m，4H)，2.298(s，3H)，2.253(m，2H)
Embodiment 7
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-5-(hydroxyl The base carbamyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters
Figure GSA00000049713000461
The first step
4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester
With zinc cyanide (3g, 26mmol) and zinc (1.7g, 26mmol) stirring and dissolving is in 100mL 4-(4-chloro-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester 1f (4g, dimethylacetamide solution 13mmol), add two (tri-butyl phosphine) palladium (664mg, 1.3mmol), 160 ℃ of following stirring reactions 8 hours.Add 250mL 10% ammoniacal liquor in 0 ℃ of downhill reaction liquid, stir and use ethyl acetate extraction (100mL * 3) after 10 minutes, merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and uses silica gel column chromatography with eluent system B purifying gained resistates, obtain title product 4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester 7a (3.0g, white solid), productive rate: 77.3%.
MS?m/z(ESI)：199.4[M-100+1]
Second step
3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl) benzonitrile
With 4-(4-cyano group-2-aminomethyl phenyl)-5, and 6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester 7a (3.7g 12.20mmol) is dissolved in 1 of 25mL 1M hydrogenchloride, in the 4-dioxane solution, and stirring reaction 12 hours.Add 20mL methyl alcohol and 100mL saturated sodium bicarbonate solution behind the reaction solution concentrating under reduced pressure, stir and use dichloromethane extraction (50mL * 3) after 10 minutes, merge organic phase, with saturated nacl aqueous solution washing (30mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, obtain title product 3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl) benzonitrile 7b crude product (2.4g, white solid), directly drop into the next step.
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the ice bath, with 3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl) (634mg 3.20mmol) is dissolved in the 10mL methylene dichloride benzonitrile 7b, add N, and the N-diisopropylethylamine (827mg, 6.40mmol) and 15mL (3aR, 5S, 6aS)-5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1r (1.1g, dichloromethane solution 3.20mmol), stirring reaction 30 minutes, stirring at room reaction 30 minutes.In reaction solution, add the 150mL methylene dichloride; use saturated ammonium chloride solution (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 7c (970mg; white solid), productive rate: 60.4%.
MS?m/z(ESI)：502.4[M+1]
The 4th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) six hydrogen ring penta [c] pyrroles-2 methyl); (970mg 1.93mmol) is dissolved in the 30mL methylene dichloride 5 (1H)-dicarboxylic acid methyl esters 7c, adds Iodotrimethylsilane (1.16g; 5.80mmol), 50 ℃ of following stirring reactions 3 hours.The reaction solution ice bath is cooled to 0 ℃; in reaction solution, add 3mL methyl alcohol; 20mL water and 40mL saturated sodium bicarbonate solution; stir after 15 minutes with dichloromethane extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (30mL * 2); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; obtain title product (3aR; 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 7d crude product (810mg; faint yellow solid), productive rate 94.6%.
MS?m/z(ESI)：444.4[M+1]
The 5th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 7d (810mg methyl); 1.83mmol) be dissolved in the 25mL methylene dichloride, add N, N-carbonyl dimidazoles (592mg; 3.65mmol), stirring reaction 12 hours.In reaction solution, add the 100mL methylene dichloride; water (50mL * 2) and saturated nacl aqueous solution washing (50mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-and 2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 7e (840mg, white solid), productive rate: 85.4%.
MS?m/z(ESI)：538.4[M+1]
The 6th step
(3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl)-six hydrogen ring penta [c] pyrroles-2 methyl); under 5 (1H)-2-carboxylic acids-((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester ice bath; with (S)-2-(methylol) tetramethyleneimine-1-benzyl carboxylate 2b (297mg; 1.26mmol) be dissolved in the 15mL tetrahydrofuran (THF); sodium hydride (the 76mg of adding 60%; 1.90mmol); stirring reaction 5 minutes adds (3aR, 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-(340mg 0.63mmol), continues to stir 30 minutes 2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 7e.Reaction solution is poured in the 50mL frozen water; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product (3aR with silica gel column chromatography; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids-((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 7f (190mg; white solid), productive rate: 42.8%.
MS?m/z(ESI)：705.5[M+1]
The 7th step
(3aR, 5R, 6aS)-2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl)-six hydrogen ring penta [c] pyrroles-2 methyl); (190mg 0.27mmol) is dissolved in 4mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1), add lithium hydroxide (113mg to 5 (1H)-2-carboxylic acids-((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 7f; 2.70mmol) and water (0.4mL), stirring reaction 12 hours.Reaction solution is poured in the 80mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter, filtrate decompression concentrates, and uses the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5R, 6aS)-2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-octahydro ring penta [c] pyrroles-5-carboxylic acid 7g (150mg; white solid), productive rate: 80.4%.
MS?m/z(ESI)：691.5[M+1]
The 8th step
(3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters ice bath under; with (3aR; 5R; 6aS)-2-((((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-octahydro ring penta [c] pyrroles-5-carboxylic acid 7g (150mg; 0.22mmol) be dissolved in 3mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (144mg; 0.33mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (45mg; 0.65mmol) and N-methylmorpholine (110mg; 1.09mmol), continue to stir 15 minutes stirring at room reaction 3 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter, filtrate decompression concentrates, and uses the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters 7 (94mg; white solid), productive rate: 60.5%.
MS?m/z(ESI)：706.5[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.462(m，1H)，7.362(m，6H)，7.160(d，1H，J＝7.6Hz)，5.596(s，1H)，5.187(s，1H)，4.219(m，4H)，3.930(m，9H)，2.821(m，2H)，2.657(d，1H，J＝9.2Hz)，2.412(m，6H)，2.009(m，4H)，1.688(m，4H)，1.320(m，2H)
Embodiment 8
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-5-(hydroxyl The base carbamyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester
Figure GSA00000049713000501
The first step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester
Under the ice bath; (98mg 1.12mmol) is dissolved in the 12mL tetrahydrofuran (THF), adds 60% sodium hydride (67mg in reaction solution with (S)-3-hydroxyl tetrahydrofuran; 1.68mmol); stirring reaction 10 minutes adds (3aR, 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-(300mg 0.56mmol), continues to stir 30 minutes 2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 7e.Reaction solution is poured in the 30mL frozen water; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product (3aR with silica gel column chromatography; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester 8a (120mg; white solid), productive rate: 38.4%.
MS?m/z(ESI)：558.4[M+1]
Second step
(3aR, 5R, 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-2-((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) six hydrogen ring penta [c] pyrroles-2 methyl); (120mg 0.22mmol) is dissolved in 3mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1), add lithium hydroxide (90mg to 5 (1H)-2-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester-5-carboxylate methyl ester 8a; 2.2mmol) and water (0.3mL), stirring reaction 12 hours.Reaction solution is poured in the 30mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and obtains title product (3aR, 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-and 2-(((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 8b (110mg, white solid) crude product, productive rate: 91.9%.
MS?m/z(ESI)：544.4[M+1]
The 3rd step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester
Under the ice bath; with (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-2-(((S)-tetrahydrofuran (THF)-3-base oxygen base) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 8b (110mg; 0.20mmol) be dissolved in 2mLN; in the dinethylformamide, and adding benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (133mg, 0.30mmol); stirring reaction 30 minutes; add oxammonium hydrochloride (42mg, 0.60mmol) and N-methylmorpholine (101mg, 1mmol); continue to stir 1 hour stirring at room reaction 2 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with 1M hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter, filtrate decompression concentrates, and uses the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-tetrahydrofuran (THF)-3-yl) ester 8 (80mg; white solid), productive rate: 71.6%.
MS?m/z(ESI)：559.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.518(m，2H)，7.166(d，1H，J＝7.6Hz)，5.622(s，1H)，5.247(s，1H)，3.969(m，5H)，3.466(m，8H)，2.933(m，2H)，2.683(d，1H，J＝9.6Hz)，2.434(m，4H)，2.305(s，3H)，2.200(m，2H)，1.864(m，2H)
Embodiment 9
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen rings penta [c] Pyrroles-2 (1H)-carboxylic acid tert-butyl ester
Figure GSA00000049713000511
Figure GSA00000049713000521
The first step
(3aR, 5S, 6aS)-5-((4-hydroxyphenyl sulphur) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Will (3aR, 5S, 6aS)-5-(iodomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1p (1.48g 4mmol) is dissolved in the 8mL tetrahydrofuran (THF), and adding 4-mercapto-phenol (1.02g, 8mmol), stirring reaction 12 hours.With the reaction solution concentrating under reduced pressure, add the 80mL methylene dichloride, successively water (30mL * 2) and saturated nacl aqueous solution washing (30mL * 2), the dichloromethane layer anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product (3aR, 5S, 6aS)-5-((4-hydroxyphenyl sulphur) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 9a (1.76g, yellow oil), crude product.
MS?m/z(ESI)：364.2[M-1]
Second step
(3aR, 5S, 6aS)-5-((4-hydroxyphenyl alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Will (3aR, 5S, 6aS)-5-((4-hydroxyphenyl sulphur) methyl) six hydrogen ring penta [c] pyrroles-2, (1.8g 4.80mmol) is dissolved in the 15mL methylene dichloride 5 (1H)-dicarboxylic acid methyl esters 9a, adds metachloroperbenzoic acid (2.5g, 14.50mmol), stirring reaction 2 hours.In reaction solution, add the 200mL methylene dichloride; use saturated sodium bicarbonate solution (50mL), saturated sodium thiosulfate solution (50mL) and saturated nacl aqueous solution washing (30mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-hydroxyphenyl alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 9b crude products (560mg, white solid), productive rate: 35.5%.
MS?m/z(ESI)：398.1[M+1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
With (3aR; 5S; 6aS)-5-((4-hydroxyphenyl alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; (504mg 1.27mmol) is dissolved in 10mLN, in the dinethylformamide to 5 (1H)-dicarboxylic acid methyl esters 9b; add cesium carbonate (1g; 3.17mmol) and 1-brombutyl-2-alkynes (253mg, 1.90mmol), stirring reaction 3 hours.The reaction solution concentrating under reduced pressure; in reaction solution, add the 50mL methylene dichloride; water (25mL * 2) and saturated nacl aqueous solution washing (25mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 9c (570mg; yellow oil), productive rate: 99.9%.
MS?m/z(ESI)：450.1[M+1]
The 4th step
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
With (3aR; 5S; 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 9c (391mg; 0.87mmol) be dissolved in the 5mL methylene dichloride; add Iodotrimethylsilane (314mg, 1.57mmol), 50 ℃ of following stirring reactions 5 hours.The reaction solution ice bath is cooled to 0 ℃; in reaction solution, add 2.5mL methyl alcohol; 10mL water and 30mL saturated sodium bicarbonate solution; stir after 15 minutes with dichloromethane extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter, filtrate decompression concentrates, and obtains title product (3aR; 5S; 6aS)-and 5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 9d crude product (383mg, yellow oil), productive rate 97.4%.
MS?m/z(ESI)：392.4[M+1]
The 5th step
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acid tert-butyl ester-5-carboxylate methyl ester
Under the ice bath; with (3aR; 5S, 6aS)-(274mg 0.70mmol) is dissolved in the 4mL methylene dichloride octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 9d 5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl); add N; the N-diisopropylethylamine (227mg, 1.75mmol) and tert-Butyl dicarbonate (230mg, 1.05mmol); stirring reaction 0.5 hour, room temperature reaction 1 hour.In reaction solution, add 40mL saturated ammonium chloride solution adjusting pH value and be about 7, with dichloromethane extraction (40mL * 3) reaction solution.Merge organic phase; with saturated nacl aqueous solution (30mL * 2); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; obtain title product (3aR; 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acid tert-butyl ester-5-carboxylate methyl ester 9e (285mg; light yellow oil), productive rate: 82.9%.
MS?m/z(ESI)：392.2[M-100+1]
The 6th step
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-2-(tertbutyloxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acid tert-butyl esters-5-carboxylate methyl ester 9e (85mg; 0.17mmol) be dissolved in 0.2mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (24mg, 0.57mmol) and water (0.1mL), stirring reaction 12 hours.In reaction solution, add Glacial acetic acid and regulate pH=5～6; add the 25mL methylene dichloride, with saturated nacl aqueous solution washing (10mL * 2), anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S; 6aS)-and 5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-2-(tertbutyloxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 9f (59mg, light yellow oil), productive rate: 72%.
MS?m/z(ESI)：376.3[M-1]
The 7th step
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-2-(tertbutyloxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 9f (59mg; 0.12mmol) be dissolved in 0.5mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (83mg; 0.19mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (26mg; 0.37mmol) and N-methylmorpholine (63mg; 0.62mmol), continue to stir 1 hour stirring at room reaction 2 hours.With the reaction solution concentrating under reduced pressure; add the 30mL methylene dichloride; water (15mL * 2) and saturated nacl aqueous solution washing (15mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-and 5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters 9 (20mg, colorless oil), productive rate: 32.8%.
MS?m/z(ESI)：393.1[M-100+1]
1H?NMR(400MHz，CDCl 3)：δ7.798-7.820(d，2H)，7.073-7.095(d，2H)，4.725-4.731(d，2H)，3.467(s，2H)，3.374-3.389(br，4H)，2.833(s，2H)，2.458-2.475(m，2H)，1.869(s，3H)，1.839(m，2H)，1.454(s，9H)
Embodiment 10
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen rings penta [c] Pyrroles-2 (1H)-carboxylate methyl ester
Figure GSA00000049713000541
The first step
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-2-(methoxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 9c (215mg; 0.48mmol) be dissolved in 2mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (60mg, 1.43mmol) and water (0.5mL), stirring reaction 12 hours.In reaction solution, add concentrated hydrochloric acid and regulate pH=2; add the 50mL methylene dichloride, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S; 6aS)-and 5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-2-(methoxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 10a (145mg, white oily matter), productive rate: 58.5%.
MS?m/z(ESI)：436.3[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylate methyl esters
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-2-(methoxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 10a (72mg; 0.17mmol) be dissolved in 1mLN; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (109mg; 0.25mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (35mg; 0.50mmol) and N-methylmorpholine (84mg; 0.83mmol), continue to stir 1 hour stirring at room reaction 2 hours.With the reaction solution concentrating under reduced pressure; regulate pH=2; add the 40mL methylene dichloride; water (25mL * 2) and saturated nacl aqueous solution washing (25mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(butyl-2-alkynyloxy base) benzenesulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylate methyl ester 10 (14mg; white solid), productive rate: 18.9%.
MS?m/z(ESI)：451.2[M-1]
1H?NMR(400MHz，CDCl 3)：δ7.807-7.829(d，2H)，7.085-7.107(d，2H)，4.737-4.742(d，2H)，3.703(s，3H)，3.434-3.469(br，6H)，2.862(s，2H)，2.458-2.508(m，2H)，1.874(s，3H)，1.837(s，2H)
Embodiment 11
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six Hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid ((R)-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters
Figure GSA00000049713000561
The first step
(R)-2-(methylol) tetramethyleneimine-1-benzyl carboxylate
Under the ice bath, with (R)-tetramethyleneimine-2-base methyl alcohol 11a (5g 49mmol) is dissolved in the 60mL methylene dichloride, add triethylamine (6.4g, 64mmol) and chloroformic acid benzyl ester (10g, 59mmol), stirring reaction 1 hour, stirring at room was reacted 12 hours.Under the ice bath reaction solution is poured in the 200mL saturated ammonium chloride solution, with dichloromethane extraction (50mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product (R)-2-(methylol) tetramethyleneimine-1-benzyl carboxylate 11b (8.0g with silica gel column chromatography, colourless liquid), productive rate: 69.6%.
MS?m/z(ESI)：236.3[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids ((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester
Under the ice bath; with (R)-2-(methylol) tetramethyleneimine-1-benzyl carboxylate 11b (698mg; 2.97mmol) be dissolved in the 15mL tetrahydrofuran (THF), add 60% sodium hydride (194mg, 4.44mmol); stirring reaction 5 minutes; add (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1u (800mg; 1.48mmol), continue to stir 40 minutes.Reaction solution is poured in the 30mL frozen water; with ethyl acetate extraction (50mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5S with silica gel column chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 11c (440mg, white solid), productive rate: 42%.
MS?m/z(ESI)：707.5[M+1]
The 3rd step
(3aR, 5S, 6aS)-2-((((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 11c (440mg; 0.62mmol) be dissolved in 10mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (262mg, 6.23mmol) and water (5mL), stirring reaction 12 hours.Reaction solution is poured in the 30mL frozen water; regulate pH=2 with hydrochloric acid; with ethyl acetate extraction (50mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with eluent system A purifying gained resistates, obtains title product (3aR with silica gel column chromatography; 5S; 6aS)-and 2-((((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 11d (335mg, light yellow solid), productive rate: 77%.
MS?m/z(ESI)：691.5[M-1]
The 4th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters
Under the ice bath; with (3aR; 5S; 6aS)-2-((((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 11d (100mg; 0.14mmol) be dissolved in 2mLN; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (127mg; 0.29mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (30mg; 0.43mmol) and N-methylmorpholine (73mg; 0.72mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters 11 (22mg, colourless sticking shape solid), productive rate: 22%.
MS?m/z(ESI)：708.5[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.477(m，2H)，7.400(m，3H)，7.351(m，3H)，5.181(m，2H)，4.500(m，2H)，3.933(d，2H，J＝11.6Hz)，3.532(m，6H)，2.883(m，4H)，2.395(s，3H)，1.975(m，4H)，1.817(m，6H)，1.681(m，6H)
Embodiment 12
(3aR, 5S, 6aS)-5-(hydroxyl amino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles -2 (1H)-carboxylate methyl esters
Figure GSA00000049713000581
The first step
4-phenylpiperazine-1-carboxylic acid tert-butyl ester
With cuprous iodide (475mg, 2.50mmol) and potassiumphosphate (10.6g 50mmol) is dissolved in the 25mL Virahol, adding piperazine-1-carboxylic acid tert-butyl ester 4a (5.6g, 30mmol), ethylene glycol (2.8mL, 50mmol) and iodobenzene (2.8mL, 25mmol), 80 ℃ of following stirring reactions 24 hours.In reaction solution, add 35mL water and 100mL ethyl acetate, with ethyl acetate extraction (60mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product 4-phenylpiperazine-1-carboxylic acid tert-butyl ester 12a (3.2g, white solid), productive rate: 48.8%.
MS?m/z(ESI)：263.2[M+1]
Second step
The 1-phenylpiperazine
With 4-phenylpiperazine-1-carboxylic acid tert-butyl ester 12a (250mg 0.95mmol) is dissolved in 1 of 20mL 1M hydrogenchloride, in the 4-dioxane solution, stirring reaction 4 hours.Add 10mL methylene dichloride and 20mL saturated sodium bicarbonate solution behind the reaction solution concentrating under reduced pressure, stir after 10 minutes with dichloromethane extraction (40mL * 3), merge organic phase, with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, obtain title product 1-phenylpiperazine 12b (120mg, white solid), productive rate: 72.9%.
MS?m/z(ESI)：163.1[M-100+1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the ice bath, (1g 6.20mmol) is dissolved in the 15mL methylene dichloride, adds N with 1-phenylpiperazine 12b, N-diisopropylethylamine (2.4g, 18.60mmol) and 15mL (3aR, 5S, 6aS)-5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1r (2.9g, dichloromethane solution 3mmol), stirring reaction 30 minutes, room temperature reaction 12 hours.In reaction solution, add 100mL water,, merge organic phase with dichloromethane extraction (50mL * 2); with saturated nacl aqueous solution washing (30mL * 2), anhydrous sodium sulfate drying, filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5S with silica gel column chromatography; 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 12c (2g, yellow viscous material), productive rate: 71.4%.
MS?m/z(ESI)：466.3[M+1]
The 4th step
(3aR, 5S, 6aS)-2-(methoxycarbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 12c (265mg; 0.57mmol) be dissolved in 3mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (72mg, 1.71mmol) and water (1.5mL), stirring reaction 12 hours.Reaction solution is poured in the 30mL frozen water; regulate pH=2 with hydrochloric acid; with ethyl acetate extraction (50mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S; 6aS)-and 2-(methoxycarbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 12d (200mg, white solid), productive rate: 77.8%.
MS?m/z(ESI)：450.2[M-1]
The 5th step
(3aR, 5S, 6aS)-5-(hydroxyl amino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylate methyl esters
Under the ice bath; with (3aR; 5S; 6aS)-2-(methoxycarbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 12d (200mg; 0.44mmol) be dissolved in 5mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (294mg; 0.66mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (93mg; 1.33mmol) and N-methylmorpholine (673mg; 6.65mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with hydrochloric acid; with ethyl acetate extraction (40mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S; 6aS)-and 5-(hydroxyl amino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylate methyl esters 12 (120mg, white solid), productive rate: 58%.
MS?m/z(ESI)：467.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.760(m，2H)，7.583(m，3H)，3.741(s，3H)，3.471(m，4H)，3.341(m，4H)，2.895(m，2H)，2.459(m，2H)，1.861(m，2H)，1.391(m，6H)
Embodiment 13
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-N 5 -hydroxy-n 2 , N 2 -diformazan Base six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides
Figure GSA00000049713000601
The first step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath; with (3aR; 5S; 6aS)-(250mg 0.56mmol) is dissolved in the 10mL methylene dichloride octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 4e 5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl), adds N; N-diisopropylethylamine (217mg; 1.68mmol) and dimethylcarbamyl chloride (150mg, 1.40mmol), stirring at room 12 hours.The reaction solution concentrating under reduced pressure; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 13a (210mg; light yellow oil), productive rate: 72.6%.
MS?m/z(ESI)：518.6[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 13a (210mg; 0.41mmol) be dissolved in 4mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (170mg; 4.06mmol) and water (0.5mL), stirring reaction 12 hours.Regulate pH=2～3 with hydrochloric acid; add the 30mL methylene dichloride; concentrating under reduced pressure; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 13b (100mg; white solid), productive rate: 49.1%.
MS?m/z(ESI)：502.3[M-1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-N 5-hydroxy-n 2, N 2-dimethyl six hydrogen ring penta [c] pyrroles-2,5 (1H)-diamide
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 13b (100mg; 0.20mmol) be dissolved in 1mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (133mg; 0.30mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (42mg; 0.60mmol) and N-methylmorpholine (101mg; 1mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.The 40mL methylene dichloride will be added in the reaction solution; water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperazine-1-base alkylsulfonyl) methyl)-N 5-hydroxy-n 2, N 2-dimethyl six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides 13 (46mg, white solid), productive rate: 44.7%.
MS?m/z(ESI)：519.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.519(s，1H)，7.500(s，1H)，7.042-7.063(d，1H)，3.413-3.518(m，8H)，3.349-3.376(m，2H)，3.064(s，4H)，2.916(s，6H)，2.878-2.896(m，2H)，2.437-2.454(m，2H)，2.346(s，3H)，1.908-1.925(m，2H)
Embodiment 14
(3aR, 5R, 6aS)-5-(hydroxyl amino formyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles -2 (1H)-carboxylate methyl esters
The first step
(3aR, 5R, 6aS)-5-(azido-methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Will (3aR, 5S, 6aS)-5-(iodomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1p (2g, 5.44mmol) and sodiumazide (530mg 8.16mmol) is dissolved in the 15mL methyl-sulphoxide, 100 ℃ of following stirring reactions 4 hours.In reaction solution, add 50mL water,, merge organic phase with ethyl acetate extraction (60mL * 3), with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with developping agent system A purifying gained resistates, obtain title product (3aR, 5R with the thin-layer chromatography chromatography, 6aS)-5-(azido-methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 14a (600mg, yellow liquid), productive rate: 40%.
MS?m/z(ESI)：283.2[M+1]
Second step
(3aR, 5R, 6aS)-5-(amino methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Will (3aR, 5R, 6aS)-5-(azido-methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 14a (600mg, 2.13mmol) and triphenylphosphine (837mg 3.19mmol) is dissolved in 10mL tetrahydrofuran (THF) and the 1mL water, 90 ℃ of down reactions 4 hours.The reaction solution concentrating under reduced pressure with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography, 5R, 6aS)-5-(amino methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 14b (450mg, light yellow liquid), productive rate: 82%.
The 3rd step
(3aR, 5R, 6aS)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
With (3aR, 5R, 6aS)-5-(amino methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 14b (450mg, 1.76mmol) and N, N-diisopropylethylamine (455mg, 3.52mmol) be dissolved in the 10mL methylene dichloride, adding 4-toluene-1-SULPHURYL CHLORIDE (503mg, 2.64mmol), stirring reaction 12 hours.In reaction solution, add 50mL water,, merge organic phase with dichloromethane extraction (50mL * 3), with saturated nacl aqueous solution washing (30mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with developping agent system A purifying gained resistates, obtain title product (3aR, 5R with the thin-layer chromatography chromatography, 6aS)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 14c (350mg, white viscous material), productive rate 48%.
MS?m/z(ESI)：411.3[M+1]
The 4th step
(3aR, 5R, 6aS)-2-(methoxycarbonyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR, 5R, 6aS)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 14c (350mg, 0.85mmol) be dissolved in 6mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1), add lithium hydroxide (107mg, 2.56mmol) and water (3mL), stirring reaction 12 hours.Regulate pH=2～3 with hydrochloric acid,, merge organic phase with ethyl acetate extraction (30mL * 3), with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates, obtain title product (3aR, 5R, 6aS)-2-(methoxycarbonyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 14d (338mg, white solid), productive rate: 99.9%.
MS?m/z(ESI)：397.3[M+1]
The 5th step
(3aR, 5R, 6aS)-5-(benzyloxy carbamyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid methyl
With (3aR, 5R, 6aS)-2-(methoxycarbonyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 14d (100mg, 0.25mmol) and 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (54mg, 0.28mmol) be dissolved in the 10mL methylene dichloride, add Phenylmethoxyamine hydrochloride (45mg, 0.28mmol) and N-methylmorpholine (28mg, 0.27mmol), stirring reaction 4 hours.The 40mL methylene dichloride will be added in the reaction solution, use hydrochloric acid (20mL * 2) successively, saturated sodium bicarbonate solution (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates, obtain title product (3aR, 5R, 6aS)-and 5-(benzyloxy carbamyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid methyl 14e (64mg, white solid), productive rate: 50.8%.
MS?m/z(ESI)：502.3[M+1]
The 6th step
(3aR, 5R, 6aS)-5-(hydroxyl amino formyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylate methyl esters
With (3aR, 5R, 6aS)-5-(benzyloxy carbamyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid methyl 14e (64mg, 0.13mmol) be dissolved in the 10mL methylene dichloride, add trifluoromethanesulfonic acid trimethylsilyl group (289mg, 1.30mmol), 50 ℃ of following stirring reactions 24 hours.The 40mL methylene dichloride will be added in the reaction solution, use hydrochloric acid (20mL * 2) successively, saturated sodium bicarbonate solution (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates, obtain title product (3aR, 5R, 6aS)-and 5-(hydroxyl amino formyl)-5-((4-aminomethyl phenyl sulfonamido) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylate methyl esters 14 (43mg, yellow sticking shape), productive rate: 81%.
MS?m/z(ESI)：412.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.759(s，2H)，7.304(s，2H)，3.687(s，3H)，3.441(s，2H)，3.349(s，2H)，2.983(s，2H)，2.718(s，2H)，2.438(s，3H)，2.139(s，2H)，1.768(s，2H)
Embodiment 15
(3aR, 5S, 6aS)-5-((4-(4-hydrogen base-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six Hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid ((R)-tetramethyleneimine-2-ylmethyl) ester
Figure GSA00000049713000631
Figure GSA00000049713000641
The first step
(3aR, 5S, 6aS)-5-((4-(4-hydrogen base-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((R)-tetramethyleneimine-2-ylmethyl) ester
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((R)-1-(carbobenzoxy-(Cbz)) tetramethyleneimine-2-yl) methyl esters 11 (170mg; 0.24mmol) be dissolved in 10mL tetrahydrofuran (THF) and water (V: V=1: in the mixed solvent 1); add trifluoroacetic acid (41mg; 0.36mmol) and 5% palladium barium sulfate (100mg), hydrogen exchange three times, stirring reaction 4 hours.Filter; filtrate is separated with the HPLC preparation; obtain title product (3aR; 5S; 6aS)-5-((4-(4-hydrogen base-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((R)-tetramethyleneimine-2-ylmethyl) ester 15 (40mg; light gray solid), productive rate: 29%.
MS?m/z(ESI)：574.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.479(s，1H)，7.582(m，2H)，4.844(m，3H)，4.273(m，2H)，3.915(m，2H)，3.579(m，4H)，2.831(m，4H)，2.410(s，3H)，2.051(m，4H)，1.694(m，4H)，1.146(m，6H)
Embodiment 16
(3aR, 5S, 6aS)-N 5 -hydroxy-n 2 , N 2 -dimethyl-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen rings penta [c] Pyrroles-2,5 (1H)-dicarboxylic acid acid amides
Figure GSA00000049713000651
The first step
(3aR, 5S, 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under 50 ℃; with (3aR; 5S; 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; (500mg 1.07mmol) is dissolved in the 15mL methylene dichloride 5 (1H)-dicarboxylic acid methyl esters 12c, adds Iodotrimethylsilane (645mg; 3.22mmol), stirring reaction 4 hours.The reaction solution ice bath is cooled to 0 ℃; in reaction solution, add 2mL methyl alcohol; 10mL water and 10mL saturated sodium bicarbonate solution; with dichloromethane extraction (50mL * 3); merge organic phase; with saturated nacl aqueous solution washing (30mL * 2); anhydrous sodium sulfate drying; filter, filtrate decompression concentrates, and obtains title product (3aR; 5S; 6aS)-and 5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 16a crude product (470mg, faint yellow solid), product is not purified directly to carry out next step reaction.
MS?m/z(ESI)：408.4[M+1]
Second step
(3aR, 5S, 6aS)-2-(dimethylamino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath; with (3aR; 5S; 6aS)-(470mg 1.07mmol) is dissolved in the 15mL methylene dichloride octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 16a 5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl), adds N; N-diisopropylethylamine (415mg; 3.21mmol) and dimethylcarbamyl chloride (173mg, 1.60mmol), stirring at room reaction 6 hours.The reaction solution concentrating under reduced pressure; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-2-(dimethylamino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 16b (330mg; yellow oily matter), productive rate: 64.4%.
MS?m/z(ESI)：479.4[M+1]
The 3rd step
(3aR, 5S, 6aS)-2-(dimethylamino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-2-(dimethylamino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 16b (330mg; 0.69mmol) be dissolved in 4mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (289mg; 6.90mmol) and water (2mL), stirring reaction 12 hours.Regulate pH=2-3 with hydrochloric acid,, merge organic phase with ethyl acetate extraction (50mL * 3); with saturated nacl aqueous solution washing (30mL * 2); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-2-(dimethylamino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 16c (120mg; white solid), productive rate: 37%.
MS?m/z(ESI)：463.3[M-1]
The 4th step
(3aR, 5S, 6aS)-N 5-hydroxy-n 2, N 2-dimethyl-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-diamide
Under the ice bath; with (3aR; 5S; 6aS)-2-(dimethylamino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 16c (120mg; 0.26mmol) be dissolved in 5mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (172mg; 0.39mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (54mg; 0.78mmol) and N-methylmorpholine (131mg; 1.30mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.Reaction solution is added in the 40mL frozen water that stirs, with ethyl acetate extraction (30mL * 3), with saturated nacl aqueous solution washing (20mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates, obtain title product (3aR, 5S, 6aS)-N 5-hydroxy-n 2, N 2-dimethyl-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides 16 (70mg, white solid), productive rate: 56%.
MS?m/z(ESI)：480.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.760(m，2H)，7.583(m，3H)，4.275(m，4H)，3.463(m，4H)，3.300(m，4H)，2.901(s，6H)，1.742(m，2H)，1.519(m，2H)，1.407(m，4H)
Embodiment 17
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl-N-hydroxyl-2-(tetramethyleneimine-1- Carbonyl) octahydro ring penta [c] pyrroles-5-acid amides
Figure GSA00000049713000671
The first step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(tetramethyleneimine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath; with (3aR; 5S; 6aS)-(194mg 0.44mmol) is dissolved in the 5mL methylene dichloride octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1t 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl), adds N in reaction solution; N-diisopropylethylamine (169mg; 1.31mmol) and tetramethyleneimine-1-carbonyl chlorine (119mg, 0.85mmol), stirring reaction 12 hours.With the reaction solution concentrating under reduced pressure; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(tetramethyleneimine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 17a (54mg; light yellow oil), productive rate: 23%.
MS?m/z(ESI)：543.4[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(tetramethyleneimine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(tetramethyleneimine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 17a (54mg; 0.10mmol) be dissolved in 0.4mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (41mg; 1mmol) and water (0.1mL), stirring reaction 12 hours.Regulate pH=3～4 with hydrochloric acid; with dichloromethane extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(tetramethyleneimine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 17b (20mg; white solid), productive rate: 37.7%.
MS?m/z(ESI)：527.4[M-1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl-2-(tetramethyleneimine-1-carbonyl) octahydro ring penta [c] pyrroles-5-acid amides
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(tetramethyleneimine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 17b (20mg; 0.05mmol) be dissolved in 0.2mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (36mg; 0.056mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (11mg; 0.16mmol) and N-methylmorpholine (28mg; 0.28mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.The reaction solution concentrating under reduced pressure; in resistates, add in the 30mL methylene dichloride; regulate pH=2; water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl-2-(tetramethyleneimine-1-carbonyl) octahydro ring penta [c] pyrroles-5-acid amides 17 (9mg; light yellow solid), productive rate: 45%.
MS?m/z(ESI)：544.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.459-7.480(d，1H)；7.432(s，2H)，7.279-7.299(d，1H)，3.866-3.895(d，2H)，3.466-3.493(d，2H)，3.372(br，8H)，2.805-2.886(br，5H)，2.381-2.401(br，2H)，2.356(s，3H)，1.650-1.818(br，10H)
Embodiment 18
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N 5 -hydroxy-n 2 , N 2 -diformazan Base six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides
Figure GSA00000049713000681
The first step
(3aR, 5R, 6aS)-5-(iodomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the dry ice bath, with (3aR, 6aS)-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 1o (3.57g, 15.70mmol) be dissolved in the 50mL tetrahydrofuran (THF), the tetrahydrofuran solution of adding 2M lithium diisopropyl amido (12mL, 23.50mmol), stirring reaction 30 minutes, add methylene iodide (8.4g, 31.40mmol), continue to stir-20 ℃ of stirring reactions 2 hours 1 hour.In reaction solution, add the 100mL saturated ammonium chloride solution,, merge organic phase with ethyl acetate extraction (100mL * 3), with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with eluent system B purifying gained resistates, obtain title product (3aR, 5R with silica gel column chromatography, 6aS)-5-(iodomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 18a (1.042g, yellow oil), productive rate: 18.05%.
MS?m/z(ESI)：368.1[M+1]
Second step
(3aR, 5R, 6aS)-5-(ethanoyl sulphomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Will (3aR, 5R, 6aS)-5-(iodomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 18a (1g 2.72mmol) is dissolved in 5mL N, in the dinethylformamide, adding acetate sulphur potassium ester (467mg, 4mmol), stirring reaction 12 hours.Reaction solution is poured in the 30mL frozen water,, merged organic phase with ethyl acetate extraction (50mL * 3) reaction solution; with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter; filtrate decompression concentrates; with eluent system B purifying gained resistates, obtain title product (3aR, 5R with silica gel column chromatography; 6aS)-5-(ethanoyl sulphomethyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 18b (980mg, faint yellow solid), productive rate: 99.9%.
MS?m/z(ESI)：316.2[M+1]
The 3rd step
(3aR, 5R, 6aS)-5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the ice bath; with chlorosuccinimide (1.5g; 11.60mmol) be dissolved in the acetonitrile solution of 6mL 2M hydrochloric acid, stirring reaction 5 minutes adds (3aR; 5R; 6aS)-and 5-(ethanoyl sulphomethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 18b (980mg, 2.79mmol); stirring reaction 10 minutes, 15 ℃ are continued to stir 30 minutes.In reaction solution, add the 50mL isopropyl ether, with saturated nacl aqueous solution (20mL * 3), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, obtain title product (3aR, 5R, 6aS)-5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 18c crude product (926mg, light yellow oil), productive rate 97.7%.
The 4th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under the ice bath, (273mg 1.37mmol) is dissolved in the 8mL methylene dichloride with 3-methyl-4-(piperidin-4-yl) benzonitrile 1i, add N, (537mg 4.11mmol), adds (3aR to N-sec.-propyl ethamine, 5R, 6aS)-and 5-(chlorine sulfonymethyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters 18c (926mg, 2.73mmol), stirring reaction 30 minutes, room temperature reaction 12 hours.With the reaction solution concentrating under reduced pressure; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 18d crude products (759mg, yellow oil).
MS?m/z(ESI)：504.4[M+1]
The 5th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 18d (759mg; 1.50mmol) be dissolved in the 20mL methylene dichloride; add Iodotrimethylsilane (1.5g, 7.50mmol), 50 ℃ of following stirring reactions 7 hours.The reaction solution ice bath is cooled to 0 ℃; in reaction solution, add 2mL methyl alcohol; 10mL water and 50mL saturated sodium bicarbonate solution; with dichloromethane extraction (50mL * 3); merge organic phase; with saturated nacl aqueous solution washing (30mL * 2); anhydrous sodium sulfate drying; filter, filtrate decompression concentrates, and obtains title product (3aR; 5R; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 18e crude product (388mg, brown solid), productive rate: 57.8%.
MS?m/z(ESI)：446.3[M+1]
The 6th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath; with (3aR; 5R; 6aS)-(255mg 0.57mmol) is dissolved in the 5mL methylene dichloride octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 18e 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl), adds N; N-diisopropylethylamine (221mg; 1.71mmol) and dimethylcarbamyl chloride (123mg, 1.14mmol), stirring at room 12 hours.The reaction solution concentrating under reduced pressure; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 18f (86mg; pale yellow oily matter), productive rate: 29.2%.
MS?m/z(ESI)：517.4[M+1]
The 7th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 18f (86mg; 0.17mmol) be dissolved in 0.6mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (70mg; 1.66mmol) and water (0.5mL), stirring reaction 12 hours.Regulate pH=2～3 with hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with eluent system A purifying gained resistates; obtain title product (3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 18g (20mg; transparent oily), productive rate: 24%.
MS?m/z(ESI)：501.3[M-1]
The 8th step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N 5-hydroxy-n 2, N 2-dimethyl six hydrogen ring penta [c] pyrroles-2,5 (1H)-diamide
Under the ice bath; with (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 18g (20mg; 0.04mmol) be dissolved in 0.2mLN; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (36mg; 0.06mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (12mg; 0.17mmol) and N-methylmorpholine (28mg; 0.28mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.With the reaction solution concentrating under reduced pressure; regulate pH=3,, merge organic phase with ethyl acetate extraction (30mL * 3); with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N 5-hydroxy-n 2, N 2-dimethyl six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides 18 (7mg, white solid), productive rate: 34.8%.
MS?m/z(ESI)：518.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.467-7.487(d，1H)，7.444(s，1H)，7.283(d，1H)，3.858-3.890(d，2H)，3.663(t，2H)，3.319-3.405(m，4H)，3.259-3.788(br，2H)，2.852(s，3H)，2.755-2.834(m，8H)，2.633-2.668(m，2H)，2.364(s，3H)，1.812(m，2H)
Embodiment 19
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl-2-(morpholine-4-carbonyl Base) octahydro ring penta [c] pyrroles-5-acid amides
Figure GSA00000049713000711
The first step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(morpholine-4-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath; with (3aR; 5S; 6aS)-(250mg 0.56mmol) is dissolved in the 5mL methylene dichloride octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1t 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl), adds N; N-diisopropylethylamine (169mg; 1.31mmol) and morpholine-4-carbonyl chlorine (169mg, 1.13mmol), stirring reaction 12 hours.With the reaction solution concentrating under reduced pressure; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(morpholine-4-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 19a (250mg; light yellow oil), productive rate: 79.9%.
MS?m/z(ESI)：559.4[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(morpholine-4-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(morpholine-4-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 19a (250mg; 0.45mmol) be dissolved in 4mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (188mg; 4.50mmol) and water (0.5mL), stirring reaction 12 hours.Regulate pH=3～4 with hydrochloric acid; with dichloromethane extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(morpholine-4-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 19b (141mg; white solid), productive rate: 58%.
MS?m/z(ESI)：543.4[M-1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) N-hydroxyl-2-(morpholine-4-carbonyl) octahydro ring penta [c] pyrroles-5-acid amides
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(morpholine-4-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 19b (141mg; 0.26mmol) be dissolved in 1mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (173mg; 0.39mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (54mg; 0.77mmol) and N-methylmorpholine (131mg; 1.30mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.The reaction solution concentrating under reduced pressure; in resistates, add the 50mL methylene dichloride; regulate pH=2; water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl-2-(morpholine-4-carbonyl) octahydro ring penta [c] pyrroles-5-acid amides 19 (45mg; white solid), productive rate: 31%.
MS?m/z(ESI)：560.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.469-7.490(s，1H)，7.444(s，1H)，7.287(s，1H)，3.875-3.906(d，2H)，3.639-3.697(m，4H)，3.439-3.492(t，2H)，3.293-3.363(m，6H)，2.886(m，1H)，2.817-2.874(m，4H)，2.381-2.431(m，2H)，2.362(s，3H)，1.784-1.871(m，4H)，1.623(s，4H)
Embodiment 20
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) N-hydroxyl Base-2-(4-methyl piperazine Piperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-acid amides
Figure GSA00000049713000721
Figure GSA00000049713000731
The first step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(4-methylpiperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath; with (3aR; 5S; 6aS)-(250mg 0.56mmol) is dissolved in the 6mL methylene dichloride octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1t 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl), adds N; N-diisopropylethylamine (217mg; 1.68mmol) and 4-methylpiperazine-1-carbonyl chlorine (218mg, 1.40mmol), stirring reaction 12 hours.With the reaction solution concentrating under reduced pressure; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(4-methylpiperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 20a (157mg; light yellow solid), productive rate: 49%.
MS?m/z(ESI)：572.4[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(4-methylpiperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(4-methylpiperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 20a (157mg; 0.27mmol) be dissolved in 4mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (115mg; 2.74mmol) and water (0.5mL), stirring reaction 12 hours.Regulate pH=3 with hydrochloric acid; with dichloromethane extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (10mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(4-methylpiperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 20b (25mg; white solid), productive rate: 16.4%.
MS?m/z(ESI)：556.4[M-1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl-2-(4-methylpiperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-acid amides
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(4-methylpiperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 20b (25mg; 0.05mmol) be dissolved in 0.7mLN; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (30mg; 0.07mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (10mg; 0.14mmol) and N-methylmorpholine (23mg; 0.23mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.The reaction solution concentrating under reduced pressure; in resistates, add in the 30mL methylene dichloride; regulate pH=2; water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl-2-(4-methylpiperazine-1-carbonyl) octahydro ring penta [c] pyrroles-5-acid amides 20 (5.2mg; white solid), productive rate: 20.3%.
MS?m/z(ESI)：573.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.513-7.527(t，2H)，7.407-7.442(m，1H)，3.819-3.850(m，2H)，3.732-3.756(t，2H)，3.385-3.494(br，6H)，3.201-3.237(m，2H)，3.124-3.133(br，2H)，2.916-2.996(br，6H)，2.863(s，3H)，2.751(br，3H)，2.412(s，3H)，2.240(br，2H)，1.764-1.842(br，4H)
Embodiment 21
(3aR, 5R, 6aS)-5-(hydroxyl amino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles -2 (1H)-carboxylic acids ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters
The first step
(3aR, 5S, 6aS)-2-(1H) imidazoles-1-carbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Will (3aR, 5S, 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 16a (1.05g; 2.60mmol) be dissolved in the 20mL methylene dichloride, add N, N-carbonyl dimidazoles (840mg; 5.20mmol), stirring reaction 12 hours.In reaction solution, add the 100mL methylene dichloride; water (20mL * 2) and saturated nacl aqueous solution washing (20mL * 2) successively; anhydrous sodium sulfate drying filters, and filtrate decompression concentrates; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-2-(1H-imidazoles-1-carbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 21a (733mg; white solid), productive rate: 56.4%.
MS?m/z(ESI)：502.3[M+1]
Second step
(3aR, 5R, 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acids ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester
Under the ice bath; with (S)-2-(methylol) tetramethyleneimine-1-carboxylate methyl ester (234mg; 1.47mmol) be dissolved in the 5mL tetrahydrofuran (THF); add 60% sodium hydride (90mg successively; 2.22mmol) and (3aR, 5S, 6aS)-2-(1H-imidazoles-1-carbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 21a (300mg; 0.74mmol), stirred 40 minutes.Reaction solution is poured in the 20mL frozen water; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with developping agent system A purifying gained resistates, obtain title product (3aR, 5R with the thin-layer chromatography chromatography; 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 21b (168mg, colorless oil), productive rate: 38%.
MS?m/z(ESI)：593.4[M+1]
The 3rd step
(3aR, 5R, 6aS)-2-((((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acids ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 21b (80mg; 0.14mmol) be dissolved in 4mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (17mg, 0.40mmol) and water (1mL), stirring reaction 12 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 2-((((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 21c (50mg, white solid), productive rate: 63.8%.
MS?m/z(ESI)：577.4[M-1]
The 4th step
(3aR, 5R, 6aS)-5-(hydroxyl amino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters
Under the ice bath; with (3aR; 5R; 6aS)-2-((((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methoxyl group) carbonyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 21c (50mg; 0.09mmol) be dissolved in 3mLN; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (58mg; 0.13mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (18mg; 0.26mmol) and N-methylmorpholine (44mg; 0.43mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 5-(hydroxyl amino formyl)-5-((4-phenylpiperazine-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters 21 (30mg, light gray solid), productive rate: 58.8%.
MS?m/z(ESI)：594.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.316(t，2H，J＝4.8Hz)，6.969(d，3H，J＝7.2Hz)，3.740(s，3H)，3.423(m，8H)，3.272(s，4H)，4.428(m，5H)，4.082(m，2H)，3.740(s，3H)，3.423(m，8H)，3.272(s，4H)，2.720(s，2H)，2.255(m，2H)，1.944(m，6H)
Embodiment 22
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six Hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters
Figure GSA00000049713000761
The first step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)--2-carboxylic acid ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester
Under the ice bath; with (S)-2-(methylol) tetramethyleneimine-1-carboxylate methyl ester (118mg; 0.74mmol) be dissolved in the 5mL tetrahydrofuran (THF), the sodium hydride of adding 60% (48mg, 1.11mmol); stirring reaction 5 minutes; add (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(1H-imidazoles-1-carbonyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1u (200mg; 0.37mmol), continue to stir 40 minutes.Reaction solution is poured in the 20mL frozen water; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with developping agent system A purifying gained resistates, obtain title product (3aR, 5R with the thin-layer chromatography chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)--2-carboxylic acid ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 22a (70mg, colourless sticking shape solid), productive rate: 30%.
MS?m/z(ESI)：631.5[M+1]
Second step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-((((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methoxyl group) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)--2-carboxylic acid ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters-5-carboxylate methyl ester 22a (70mg; 0.11mmol) be dissolved in 4mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (10mg, 0.22mmol) and water (1mL), stirring reaction 12 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (20mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-((((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methoxyl group) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 22b (46mg, white solid), productive rate: 67.6%.
MS?m/z(ESI)：615.6[M-1]
The 3rd step
(3aR, 5R, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters
Under the ice bath; with (3aR; 5R; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-((((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methoxyl group) carbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 22b (50mg; 0.086mmol) be dissolved in 2mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (50mg; 0.11mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (16mg; 0.22mmol) and N-methylmorpholine (38mg; 0.38mmol), continue to stir 0.5 hour stirring at room reaction 2 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with hydrochloric acid; with ethyl acetate extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5R; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acids ((S)-1-(methoxycarbonyl) tetramethyleneimine-2-yl) methyl esters 22 (20mg, white solid), productive rate: 42.2%.
MS?m/z(ESI)：632.5[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.581(m，2H)，7.335(s，1H)，3.940(d，2H，J＝11.2Hz)，3.747(s，3H)，3.456(m，6H)，2.917(m，4H)，2.480(m，2H)，2.401(s，3H)，1.724(m，16H)
Embodiment 23
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-N 5 -hydroxyl Base-N 2 , N 2 -dimethyl-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides
The first step
(3aR, 6aS)-5-cyano group-N, N-dimethyl six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid amides
Under the dry ice bath, with (3aR, 6aS)-N, N-dimethyl-5-octahydro ring penta [c] pyrroles-2 (1H)-carboxylic acid amide 23a (10g, 51mmol) (15g 76.40mmol) is dissolved in the 100mL glycol dimethyl ether with tolysulfonyl methyl isonitrile 23b, drip 100mL potassium tert.-butoxide (12g, t-butanol solution 102mmol), 0 ℃ of following stirring reaction 2 hours, stirring at room reaction 12 hours.With reacting liquid filtering, filtrate decompression concentrates, and uses silica gel column chromatography with eluent system A purifying gained resistates, obtain title product (3aR, 6aS)-5-cyano group-N, N-dimethyl six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid amide 23c (6.0g, brown oil), productive rate: 56.9%.
MS?m/z(ESI)：208.2[M+1]
Second step
(3aR, 6aS)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Will (3aR, 6aS)-5-cyano group-N, (6g 29mmol) be dissolved in the 45mL methyl alcohol N-dimethyl six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid amide 23c, drips the vitriol oil (9mL), 90 ℃ of following stirring reactions 12 hours.In reaction solution, add the 2M sodium hydroxide solution and regulate pH=10～11, filter, filtrate decompression concentrates, add the 50mL water dissolution, with ethyl acetate extraction (100mL * 3), merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product (3aR, 6aS)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23d (3.31g, brown oil), productive rate: 47.55%.
MS?m/z(ESI)：241.2[M+1]
The 3rd step
(3aR, 5S, 6aS)-2-(dimethylamino formyl)-5-(iodomethyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the dry ice bath, with (3aR, 6aS)-(3.13g 13mmol) is dissolved in the 30mL tetrahydrofuran (THF) 2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23d, adds the tetrahydrofuran solution 4.2mL of 2M lithium diisopropyl amido, 52.16mmol), stirring reaction 30 minutes adds 20mL methylene iodide (13mL, tetrahydrofuran solution 26mmol), continue to stir-20 ℃ of stirring reactions 2 hours 1 hour.In reaction solution, add the 50mL saturated ammonium chloride solution, with ethyl acetate extraction (100mL * 3) reaction solution, merge organic phase, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product (3aR, 5S, 6aS)-2-(dimethylamino formyl)-5-(iodomethyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23e (1.73g, orange), productive rate: 34.97%.
MS?m/z(ESI)：381.1[M+1]
The 4th step
(3aR, 5S, 6aS)-5-(acetyl thio methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Will (3aR, 5S, 6aS)-2-(dimethylamino formyl)-5-(iodomethyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23e (1.73g, 4.54mmol) be dissolved in 8mL N, in the dinethylformamide, add acetate sulphur potassium ester (780mg, 6.82mmol), stirring reaction 12 hours.Reaction solution is poured in the 30mL frozen water,, merged organic phase with ethyl acetate extraction (50mL * 3) reaction solution, with saturated nacl aqueous solution washing (50mL * 2), anhydrous sodium sulfate drying filters, and filtrate decompression concentrates, with silica gel column chromatography with eluent system A purifying gained resistates, obtain title product (3aR, 5S, 6aS)-5-(acetyl thio methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23f (1.49g, brown oil), productive rate: 99.9%.
MS?m/z(ESI)：329.1[M+1]
The 5th step
(3aR, 5S, 6aS)-5-(chlorine sulfonymethyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath, with chlorosuccinimide (1.3g, 9.75mmol) be dissolved in the acetonitrile solution of 12mL 2M hydrochloric acid, stirring reaction 5 minutes adds 8.0mL (3aR, 5S, 6aS)-5-(acetyl thio methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23f (800mg, 2.43mmol) acetonitrile solution, stirring reaction 10 minutes, 15 ℃ of stirring reactions 20 minutes.In reaction solution, add the 30mL isopropyl ether, with saturated nacl aqueous solution (30mL * 3), anhydrous sodium sulfate drying, filter, filtrate decompression concentrates, and obtains title product (3aR, 5S, 6aS)-and 5-(chlorine sulfonymethyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23g crude product (500mg, pale yellow crystal), 58.45%.
The 6th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath, with 3-methyl-4-(1,2,3,6-tetrahydropyridine-4-yl) (309mg 1.56mmol) is dissolved in the 5mL methylene dichloride benzonitrile 7b, add N, the N-diisopropylethylamine (550mg, 4.26mmol) and 10mL (3aR, 5S, 6aS)-5-(chlorine sulfonymethyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23g (500mg, 1.42mmol) dichloromethane solution, stirring reaction 30 minutes, room temperature reaction 12 hours.The reaction solution concentrating under reduced pressure; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-and 2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23h (226mg, brown yellow solid), productive rate: 87.9%.
MS?m/z(ESI)：515.4[M+1]
The 7th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23h (113mg; 0.22mmol) be dissolved in 2mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add sodium hydroxide (90mg, 2.2mmol) and water (0.24mL), stirring reaction 12 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with 1M hydrochloric acid; with dichloromethane extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter, filtrate decompression concentrates, and uses the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 23i (27mg; oily matter), productive rate: 24.5%.
MS?m/z(ESI)：501.2[M+1]
The 8th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-N 5-hydroxy-n 2, N 2-dimethyl-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5; 6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 23i (27mg; 0.05mmol) be dissolved in 2mLN; in the dinethylformamide, and adding benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (36mg, 0.08mmol); stirring reaction 15 minutes; add oxammonium hydrochloride (11mg, 0.16mmol) and N-methylmorpholine (28mg, 0.27mmol); continue to stir 1 hour stirring at room reaction 3 hours.Reaction solution is poured in the 20mL frozen water, regulated pH=2, with dichloromethane extraction (30mL * 3) with 1M hydrochloric acid; merge organic phase; with saturated nacl aqueous solution washing (15mL * 2), anhydrous sodium sulfate drying, filter; filtrate decompression concentrates; with developping agent system A purifying gained resistates, obtain title product (3aR, 5S with the thin-layer chromatography chromatography; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-Ji alkylsulfonyl) methyl)-N 5-hydroxy-n 2, N 2-dimethyl-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides 23 (18mg, white solid), productive rate: 64.7%.
MS?m/z(ESI)：516.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.479-7.568(m，2H)，7.186-7.204(d，1H)，5.658(s，1H)，3.975(s，2H)，3.435-3.512(br，8H)，2.892-2.956(br，6H)，2.719(br，2H)，2.468(s，4H)，2.344(s，3H)，1.891(br，2H)
Embodiment 24
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N 5 -hydroxy-n 2 , N 2 -diformazan Base-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides
Figure GSA00000049713000811
The first step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester
Under the ice bath, with 3-methyl-4-(piperidin-4-yl) benzonitrile 1i (318mg, 1.59mmol) be dissolved in the 5mL methylene dichloride, add N, N-diisopropylethylamine (616mg, 4.77mmol) and 10mL (3aR, 5S, 6aS)-5-(chlorine sulfonymethyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 23g (560mg, dichloromethane solution 1.59mmol), continue to stir 30 minutes stirring at room reaction 12 hours.The reaction solution concentrating under reduced pressure; with silica gel column chromatography with eluent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 24a (464mg; brown oil), productive rate: 56.5%.
MS?m/z(ESI)：517.2[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 24a (440mg; 0.85mmol) be dissolved in 2.2mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add sodium hydroxide (160mg; 8.50mmol) and water (45 μ L), stirring reaction 12 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with concentrated hydrochloric acid; with dichloromethane extraction (30mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 24b (57mg, white oily matter), productive rate: 26.6%.
MS?m/z(ESI)：503.4[M+1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N 5-hydroxy-n 2, N 2-dimethyl-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-2-(dimethylamino formyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 24b (32mg; 0.06mmol) be dissolved in 0.8mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (47mg; 0.11mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (15mg; 0.21mmol) and N-methylmorpholine (35mg; 0.35mmol), continue to stir 1 hour stirring at room reaction 3 hours.With the reaction solution concentrating under reduced pressure, with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates, obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N 5-hydroxy-n 2, N 2-dimethyl-six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid acid amides 24 (10mg, white solid), productive rate: 21.6%.
MS?m/z(ESI)：518.4[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.466-7.485(d，1H)，7.439(s，1H)，7.291(s，1H)，3.880-3.907(d，2H)，3.453-3.481(d，2H)，3.346(br，4H)，2.880(s，6H)，2.861(br，5H)，2.414(br，2H)，2.363(s，3H)，1.889(m，2H)，1.811(br，4H)
Embodiment 25
(3aR, 5S, 6aS)-5-((4-luorobenzyl alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)- Carboxylate methyl ester
The first step
(3aR, 5S, 6aS)-5-((4-luorobenzyl alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-dicarboxylic acid methyl esters
Under 60 ℃, with 4-(4-chloro-2-aminomethyl phenyl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester 1f (386mg, 1.14mmol) be dissolved in self-control S-WAT/Sodium phosphate dibasic (2: 1) solution (2.4mL, 1.14mmol) in, stirring reaction 4 hours drips 2.1mL 1-brooethyl-4-fluorobenzene 25a (214mg, 1.14mmol) acetone soln, stirring reaction 12 hours.The reaction solution concentrating under reduced pressure is removed acetone and most of water, with dichloromethane extraction (30mL * 3), merges organic phase; with saturated nacl aqueous solution washing (15mL * 2), anhydrous sodium sulfate drying, filter; filtrate decompression concentrates; with eluent system A purifying gained resistates, obtain title product (3aR, 5S with silica gel column chromatography; 6aS)-5-((4-luorobenzyl alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 25b (255mg, yellowish solid), productive rate: 54.25%.
MS?m/z(ESI)：414.3[M+1]
Second step
(3aR, 5S, 6aS)-5-((4-luorobenzyl alkylsulfonyl) methyl)-2-(methoxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid
With (3aR; 5S; 6aS)-5-((4-luorobenzyl alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-dicarboxylic acid methyl esters 25b (59mg; 0.14mmol) be dissolved in 0.2mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (21mg, 0.5mmol) and water (0.1mL), stirring reaction 12 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=2 with concentrated hydrochloric acid; with dichloromethane extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S; 6aS)-and 5-((4-luorobenzyl alkylsulfonyl) methyl)-2-(methoxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 25c (23mg, white solid), productive rate: 18.7%.
MS?m/z(ESI)：398.2[M-1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-luorobenzyl alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylate methyl esters
Under the ice bath; with (3aR; 5S; 6aS)-5-((4-luorobenzyl alkylsulfonyl) methyl)-2-(methoxycarbonyl) octahydro ring penta [c] pyrroles-5-carboxylic acid 25c (23mg; 0.057mmol) be dissolved in 0.5mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (38mg; 0.85mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (12mg; 0.17mmol) and N-methylmorpholine (29mg; 0.29mmol), continue to stir 1 hour stirring at room reaction 3 hours.The reaction solution concentrating under reduced pressure is removed most of solvent; with dichloromethane extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-luorobenzyl alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylate methyl ester 25 (10mg; pale yellow solid), productive rate: 42%.
MS?m/z(ESI)：415.3[M+1]
1H?NMR(400MHz，CDCl 3)：δ7.424(s，2H)，7.093(t，2H)，4.235(s，2H)，3.688(s，3H)，3.295(s，2H)，2.746(s，2H)，2.352(br，2H)，1.882(br，2H)
Embodiment 26
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl octahydro ring penta [c] Pyrroles-5-carboxylic acid amide hydrochloride
Figure GSA00000049713000831
Figure GSA00000049713000841
The first step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2,5 (1H)-2-carboxylic acid tert-butyl ester-5-carboxylate methyl ester
Under the ice bath; with (3aR; 5S, 6aS)-(150mg 0.34mmol) is dissolved in the 5mL methylene dichloride octahydro ring penta [c] pyrroles-5-carboxylate methyl ester 1t 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl); add N; the N-diisopropylethylamine (109mg, 0.85mmol) and tert-Butyl dicarbonate (110mg, 0.50mmol); stirring reaction 0.5 hour, room temperature reaction 12 hours.The reaction solution concentrating under reduced pressure; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acid tert-butyl esters-5-carboxylate methyl ester 26a (135mg, white solid), productive rate: 72.9%.
MS?m/z(ESI)：446.5[M-100+1]
Second step
(3aR, 5S, 6aS)-2-(tertbutyloxycarbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-5-carboxylic acids
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-2; 5 (1H)-2-carboxylic acid tert-butyl esters-5-carboxylate methyl ester 26a (135mg; 0.25mmol) be dissolved in 1mL tetrahydrofuran (THF) and methyl alcohol (V: V=1: in the mixed solvent 1); add lithium hydroxide (52mg, 1.23mmol) and water (0.2mL), stirring reaction 12 hours.Reaction solution is poured in the 20mL frozen water; regulate pH=3 with concentrated hydrochloric acid; with dichloromethane extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates, and with developping agent system A purifying gained resistates, obtains title product (3aR with the thin-layer chromatography chromatography; 5S; 6aS)-and 2-(tertbutyloxycarbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-5-carboxylic acid 26b (77mg, white solid), productive rate: 58.5%.
MS?m/z(ESI)：531.4[M-1]
The 3rd step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl esters
Under the ice bath; with (3aR; 5S; 6aS)-2-(tertbutyloxycarbonyl)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl) six hydrogen ring penta [c] pyrroles-5-carboxylic acid 26b (77mg; 0.15mmol) be dissolved in 1mL N; in the dinethylformamide; add benzotriazole-1-base oxygen base three (dimethylamino) phosphine hexafluorophosphate (96mg; 0.21mmol), stirring reaction 15 minutes adds oxammonium hydrochloride (30mg; 0.44mmol) and N-methylmorpholine (73mg; 0.73mmol), continue to stir 1 hour stirring at room reaction 3 hours.The reaction solution concentrating under reduced pressure is removed most of solvent; with dichloromethane extraction (20mL * 3); merge organic phase; with saturated nacl aqueous solution washing (15mL * 2); anhydrous sodium sulfate drying; filter; filtrate decompression concentrates; with the thin-layer chromatography chromatography with developping agent system A purifying gained resistates; obtain title product (3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 26c (45mg; pale yellow solid), productive rate: 56.7%.
MS?m/z(ESI)：491.3[M-57]
The 4th step
(3aR, 5S, 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl octahydro ring penta [c] pyrroles-5-carboxylic acid amide hydrochloride
With (3aR; 5S; 6aS)-5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-5-(hydroxyl amino formyl) six hydrogen ring penta [c] pyrroles-2 (1H)-carboxylic acid tert-butyl ester 26c (45mg; 0.08mmol) be dissolved in the 2mL methylene dichloride; in reaction solution, drip 1 of 6mL 1M hydrogenchloride; the 4-dioxane solution, stirring reaction 12 hours.Reaction solution is centrifugal; add the 10mL washed with dichloromethane after getting supernatant liquid; add the 10mL washed with dichloromethane again behind the centrifuging and taking supernatant liquid; centrifugal again, discard dichloromethane layer, solid is spin-dried for and obtains title product (3aR; 5S; 6aS)-and 5-((4-(4-cyano group-2-aminomethyl phenyl) piperidines-1-base alkylsulfonyl) methyl)-N-hydroxyl octahydro ring penta [c] pyrroles-5-carboxylic acid amide hydrochloride 26 (14mg, white solid), productive rate: 36%.
MS?m/z(ESI)：447.3[M-36.5+1]
1H?NMR(400MHz，CDCl 3)：δ7.519(s，2H)，7.344-7.365(d，1H)，3.684-3.751(d，2H)，3.454(s，2H)，3.272-3.365(m，2H)，3.194-3.217(d，2H)，3.090(br，2H)，2.897-2.997(m，3H)，2.382-2.415(m，2H)，2.312(s，3H)，1.699-1.857(m，4H)，1.617-1.671(m，2H)
Test case:
Biological assessment
Example 1 The compounds of this invention suppresses to measure to the ADAMs protease activity
Method described below can be used to measure the inhibition ability of The compounds of this invention to the ADAMs protease activity, and with the half-inhibition concentration IC of compound 50(enzymic activity is suppressed to 50% o'clock required compound concentration) expression, IC 50Value is to calculate by measuring after the testing compound hybrid reaction with a certain amount of ADAMs and specific substrates and different concns.ADAM10 that this experiment is used and ADAM17 are that the recombinant human source protein (is purchased the 936-AD-020 in RnDsystems ADAM 10cat.No; ADAM 17cat.No 930-ADB-010), this enzyme is containing 25mM Tris, 2.5uM ZnCl 20.005%Brij35, the test-compound of the buffered soln of pH 9.0 and peptide substrate and different concns reacts (37 ℃ jointly under the lucifuge condition, ADAM10 reaction 4 hours, ADAM17 reaction 1 hour), subsequently at Ex320nm, read each hole fluorescent value under the Em405nm, calculate the inhibiting rate of compound, and calculate the IC of compound for the ADAMs protease activity 50Value.
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.
Table 1
The embodiment numbering IC 50(ADAM10)(nM)
1 16
2 13
3 22
4 46
5 42
6 61
7 11
11 8
12 8
13 54
15 7
16 28
17 20
18 39
19 80
20 34
21 17
22 6
23 42
24 16
26 9
Table 2
The embodiment numbering IC 50(ADAM17)(nM)
7 222
13 865
20 223
23 985
26 170
Conclusion: the most of embodiment compound of the present invention has obvious restraining effect to the ADAM10 protease activity, simultaneously the inhibition of ADAM10 is had the specificity of height.
Example 2: The compounds of this invention suppresses to measure to the propagation of HER-2 high expressing cell
Following method can be used to measure the restraining effect of The compounds of this invention to the ADAM10 in the cell of high expression level Her-2 acceptor, with enzyme linked immunological precipitation (ELISA) method, cell by detection by quantitative high expression level Her-2 acceptor is discharged into the p95 in the substratum in culturing process, this is by the hydrolysate of the Her-2 acceptor born of the same parents ectodomain of ADAM10 mediation, the restraining effect of indirect measurement compound ADAM10 in the pair cell under conditions in vitro.
With the human breast cancer cell strain SK-BR-3 cell (purchasing biology) of high expression level Her-2 acceptor in Institute ofbiochemistry and cell with 80, the concentration of 000/mL is inoculated in the 96 porocyte culture plates, use RPMI1640 substratum (Gibco cat.No 23400021) and additional 10% foetal calf serum as perfect medium, in 37 ℃, 5%CO 2Overnight incubation under the condition makes cell attachment.Subsequently original substratum is replaced by fresh RPMI1640 substratum and rests in the base foetal calf serum concentration and reduce to 1%.Test compounds is to the required a series of gradient concentration solution (as the final concentration of test compounds in cell is 100 μ M, 10 μ M, 1 μ M, 0.1 μ M, 0.01 μ M, 0.001 μ M) of experiment by DMSO dissolving back with the dilution of RPMI1640 substratum earlier.With 96 orifice plate cultured continuously after 72 hours, draw cell culture medium, after 4 times of fresh RPMI1640 substratum dilutions, with c-erbB2/c-neu rapid format ELISA kit (CALBIOCHEM, Cat.No.QIA10) to carrying out detection by quantitative via the p95 fragment that produces behind the ADAM10 excision Her-2ectodomain in the substratum, the computerized compound excises the inhibiting rate of process to the Her-2ectodomain hydrolysis of ADAM10 mediation and calculates the IC of test compounds 50Value.
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.
Table 3
The embodiment numbering IC 50(SK-BR-3)(nM)
1 18
2 6
3 9
4 42
6 33
11 16
15 6
17 6.8
18 4
19 1
20 20
21 9.8
22 1
23 54
24 7
Conclusion: the most of embodiment compound of the present invention has proliferation inhibition activity significantly to the SK-BR-3 cell.

Claims (18)

1. the compound shown in the general formula (I) or its pharmaceutically useful salt:
Wherein:
R 1Be selected from alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, aralkyl or-NR 5R 6, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or aralkyl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 2And R 3Independently be selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxyl group, cycloalkyl or heterocyclic radical separately, wherein said alkyl, alkoxyl group, cycloalkyl or heterocyclic radical optional further by one or more be selected from halogen, alkyl, alkoxyl group, carboxylic acid, carboxylicesters or-NR 5R 6Substituting group replace;
Perhaps, R 2Or R 3Can form with the carbon atom that is connected-C=O ,-C=C (R 8R 9), cycloalkyl or heterocyclic radical, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described cycloalkyl or heterocyclic radical are optional is further replaced by one or more substituting groups that are selected from halogen, hydroxyl, nitro, cyano group or alkyl;
R 4Be selected from hydrogen atom, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical ,-C (O) NR 5R 6,-S (O) 2NR 5R 6,-C (O) OR 7Or-C (O) R 7, wherein said alkyl, alkoxyl group, cycloalkyl or heterocyclic radical optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters ,-NR 5R 6Or-OR 7Substituting group replace;
R 5And R 6Independently be selected from hydrogen atom, halogen, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further by one or more R aSubstituting group replaces;
Perhaps, R 5And R 6Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical is optional further by one or more R aSubstituting group replaces;
R 7Be selected from hydrogen atom, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from hydroxyl, halogen, nitro, cyano group, alkyl, alkoxyl group, heterocyclic radical, aryl, heteroaryl, carboxylic acid, carboxylicesters or-NR 5R 6Substituting group replace;
R 8And R 9Independently be selected from hydrogen atom, alkyl, thiazolinyl, alkynyl, cycloalkyl, heterocyclic radical, carboxylic acid or carboxylicesters separately, wherein said alkyl, thiazolinyl, alkynyl, cycloalkyl or heterocyclic radical optional further by one or more be selected from halogen, nitro, cyano group, alkyl, alkoxyl group, heterocyclic radical, aryl, heteroaryl, carboxylic acid, carboxylicesters or-NR 5R 6Substituting group replace;
R aBe selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-C (O) OR 7,-OC (O) R 7,-O (CH 2) qC (O) OR 7,-S (O) pR 7,-C (O) R 7,-OS (O) OR 7,-NHC (O) R 7,-NR 10R 11,-OC (O) NR 10R 11Or-S (O) ONR 10R 11, wherein alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-C (O) OR 7,-OC (O) R 7,-O (CH 2) qC (O) OR 7,-S (O) pR 7,-C (O) R 7,-OS (O) OR 7,-NHC (O) R 7,-NR 10R 11,-OC (O) NR 10R 11Or-S (O) ONR 10R 11Substituting group replace;
R 10And R 11Independently be selected from hydrogen atom, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optional further by one or more R bSubstituting group replaces;
Perhaps, R 10And R 11Form heterocyclic radical with the nitrogen-atoms that is connected, wherein said heterocyclic radical contains one or more N, O or S (O) pHeteroatoms, and described heterocyclic radical is optional further by one or more R bSubstituting group replaces;
R bBe selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 10R 11,-OC (O) NR 10R 11,-S (O) ONR 10R 11,-C (O) R 7,-C (O) OR 7,-OC (O) R 7,-O (CH 2) qC (O) OR 7,-S (O) pR 7,-OS (O) OR 7Or-NHC (O) R 7, wherein alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-OR 7,-NR 12R 13,-OC (O) NR 12R 13,-S (O) ONR 12R 13,-C (O) R 7,-C (O) OR 7,-OC (O) R 7,-O (CH 2) qC (O) OR 7,-S (O) pR 7,-OS (O) OR 7Or-NHC (O) R 7Substituting group replace;
R 12And R 13Independently be selected from hydrogen atom, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately;
M is 1 or 2;
N is 0 or 1;
P is 0,1 or 2; And
Q is 0,1 or 2.
2. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, comprising the compound shown in the general formula (II) or its pharmaceutically useful salt:
Figure FSA00000049712900031
3. the compound shown in the general formula according to claim 1 and 2 (I) or its pharmaceutically useful salt comprise the compound shown in the following general formula (III) or its pharmaceutically useful salt:
4. the compound shown in the general formula according to claim 1 and 2 (I) or its pharmaceutically useful salt comprise the compound shown in the following general formula (IV) or its pharmaceutically useful salt:
Figure FSA00000049712900033
5. the compound shown in the general formula according to claim 1 (I) or its pharmaceutically useful salt, wherein said compound comprises:
Figure FSA00000049712900034
Figure FSA00000049712900051
6. one kind prepares the compound shown in the general formula according to claim 1 (I) or the method for its pharmaceutically useful salt, and this method comprises general formula (IA) compound
Optionally hydrolyse becomes carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (I) compound;
Wherein:
M, n, R 1～R 4Definition such as claim 1 described in,
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace; R 7Definition such as claim 1 described in.
7. method for preparing general formula according to claim 2 (II) compound or its pharmaceutically useful salt, this method comprise general formula (IIA) compound,
Figure FSA00000049712900053
Optional its is hydrolyzed into carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (II) compound;
Wherein:
M, n, R 1～R 4Definition such as claim 2 described in,
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as claim 2 described in.
8. method for preparing general formula according to claim 3 (III) compound or its pharmaceutically useful salt, this method comprises compound a
Figure FSA00000049712900061
With formula (CHR 2R 3) m-PG 2Reaction obtains product b;
Then optional with product b
Figure FSA00000049712900062
Through thio reaction, further be converted into sulfuryl c;
And then with product c
Figure FSA00000049712900063
The optional reaction under alkaline condition with formula R-H obtains general formula (IIIA);
Then with product general formula (IIIA)
Optionally hydrolyse becomes carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (III) compound;
Wherein:
M, G, R 1～R 4Definition such as claim 3 described in; PG is selected from leavings group, is preferably I, Br, Cl or methylsulfonyl; G ' is selected from halogen, hydroxyl or alkyl.
9. method for preparing general formula according to claim 3 (III) compound or its pharmaceutically useful salt, this method comprises compound b
Figure FSA00000049712900071
Obtain product d with formula R-SH reaction;
Then with product d
Figure FSA00000049712900072
Choose that general-S-is converted into sulfuryl e under suitable condition wantonly;
Then with product e
Figure FSA00000049712900073
Optionally hydrolyse becomes carboxylic acid, with azanol or hydroxylammonium salt reaction, obtains general formula (III) compound;
Wherein:
M, G, R 1～R 4Definition such as claim 3 described in; PG is selected from leavings group, is preferably I, Br, Cl or methylsulfonyl.
10. the compound shown in the general formula (IA) or its pharmaceutically useful salt, it is as the intermediate of preparation general formula according to claim 1 (I) compound or its pharmaceutically useful salt:
Wherein:
M, n, R 1～R 4Definition such as claim 1 described in;
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as claim 1 described in.
11. the compound shown in the general formula according to claim 10 (IA) or its pharmaceutically useful salt, comprising the described compound of general formula (IIA) or its pharmaceutically useful salt, it is as the intermediate of preparation general formula (II) compound or pharmaceutically acceptable salt thereof:
Wherein:
M, n, R 1～R 4Definition such as claim 2 described in;
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as claim 2 described in.
12. the compound shown in the general formula according to claim 10 (IA) or its pharmaceutically useful salt, comprising the described compound of general formula (IIIA) or its pharmaceutically useful salt, it is as the intermediate of preparation general formula (III) compound or pharmaceutically acceptable salt thereof:
Figure FSA00000049712900082
Wherein:
M, R 1～R 4Definition such as claim 3 described in;
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as claim 3 described in.
13. according to compound or its pharmaceutically useful salt shown in each described general formula (IA) of claim 10～12, wherein said compound comprises:
Figure FSA00000049712900091
14. compound or its pharmaceutically useful salt shown in the general formula a:
Figure FSA00000049712900112
Wherein:
R 4Definition such as claim 3 described in;
G is selected from hydrogen atom, alkyl, cycloalkyl or aryl, wherein said alkyl, cycloalkyl or aryl optional further by one or more be selected from halogen, hydroxyl, nitro, cyano group, alkyl, aryl, heteroaryl, carboxylic acid, carboxylicesters or-OR 7Substituting group replace;
R 7Definition such as claim 3 described in.
15. the compound shown in the general formula a according to claim 14 or its pharmaceutically useful salt, wherein said compound comprises:
Figure FSA00000049712900121
16. a pharmaceutical composition, its contain the treatment effective dose according to each described compound of claim 1～5 or its pharmaceutically useful salt and pharmaceutically useful carrier or vehicle.
17. according to compound or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～5, the purposes of pharmaceutical composition according to claim 16 in the medicine of preparation treatment metalloprotease diseases associated, wherein said metalloprotease is selected from ADAM10.
18. according to compound or its pharmaceutically useful salt shown in each described general formula (I) of claim 1～5, the purposes of pharmaceutical composition according to claim 16 in the medicine of preparation treatment cancer, wherein said cancer is lung cancer, mammary cancer, epidermis squama cancer or cancer of the stomach.
CN201010137007XA 2010-03-29 2010-03-29 Azabicyclooctane hydroximic acid derivatives, preparation method thereof, and application thereof in medicament Pending CN102206206A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102827064A (en) * 2012-08-14 2012-12-19 华东师范大学 Synthetic method for aza-bicyclo octane[3.3.0] derivatives
US9150865B2 (en) 2010-11-09 2015-10-06 The University Of Chicago Role of ADAM10 and its relevance to disease and therapeutics
CN111606970A (en) * 2020-06-05 2020-09-01 中国药科大学 1, 5-diazabicyclo [5,3,0] deca-alkanone amino acid derivative and preparation method and application thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9150865B2 (en) 2010-11-09 2015-10-06 The University Of Chicago Role of ADAM10 and its relevance to disease and therapeutics
CN102827064A (en) * 2012-08-14 2012-12-19 华东师范大学 Synthetic method for aza-bicyclo octane[3.3.0] derivatives
CN111606970A (en) * 2020-06-05 2020-09-01 中国药科大学 1, 5-diazabicyclo [5,3,0] deca-alkanone amino acid derivative and preparation method and application thereof
CN111606970B (en) * 2020-06-05 2023-04-25 中国药科大学 1, 5-diazabicyclo [5,3,0] decarenone amino acid derivative and preparation method and application thereof

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