CN1914192A - Methods for making 4-tetrazolyl-4-phenylpiperidine compounds - Google Patents

Methods for making 4-tetrazolyl-4-phenylpiperidine compounds Download PDF

Info

Publication number
CN1914192A
CN1914192A CN 200580003522 CN200580003522A CN1914192A CN 1914192 A CN1914192 A CN 1914192A CN 200580003522 CN200580003522 CN 200580003522 CN 200580003522 A CN200580003522 A CN 200580003522A CN 1914192 A CN1914192 A CN 1914192A
Authority
CN
China
Prior art keywords
compound
chemical formula
formula
reaction
make
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN 200580003522
Other languages
Chinese (zh)
Inventor
凯文·布朗
蒂莫西·J·多伊尔
约翰·W·F·怀特黑德
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Euro Celtique SA
Original Assignee
Euro Celtique SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Euro Celtique SA filed Critical Euro Celtique SA
Publication of CN1914192A publication Critical patent/CN1914192A/en
Pending legal-status Critical Current

Links

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Methods, composition, and intermediates are disclosed that are useful for making 4-Tetrazolyl-4-phenylpiperidine Compounds according to Formula (I), where Ar<1> is -C3-C8 cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or -(5-7-membered) heteroaryl, each being unsubstituted or substituted with one or more R<2> groups; Ar<2> is phenyl, naphthyl, anthryl, phenanthryl or -(5-7-membered) heteroaryl, each being unsubstituted or substituted with one or more R<2> groups; Z<1> and Z<2> are each independently a -(C1-C4 alkyl) group; R<1> is -(CH2)nC(O)N(R<3>)(R<4>) where R<3> and R<4> are each independently H or -(C1-C4 alkyl); R<2> is halogen, -C1-C3 alkyl, -O-(C1-C3 alkyl), -NH(C1-C3 alkyl) or -N(C1-C3 alkyl)2; n is an integer ranging from 1 to 4; m is an integer ranging from 0 to 4; and, in certain embodiments, the phenyl moiety attached to the 4-position of the piperidine ring of a compound according to formula (I) can be optionally substituted with one or mor R<2> groups.

Description

The preparation method of 4-tetrazyl-4-Phenylpiperidine compound
Technical field
The present invention relates to be used to prepare 4-tetrazyl-4-Phenylpiperidine compound compositions, intermediate and method.
Background technology
Pain is the common sympton that the patient seeks medical advice and treatment.Pain can be acute or chronic.Acute pain is self limiting normally, and sustainable three months of chronic pain or longer time, and cause patient's personality, mode of life, Functional Capability or overall quality of the life that (K.M.Foley takes place obviously to change, Pain, in CecilTextbook of Medicine 100-107, J.C.Bennett and E.Plum eds., 20 ThEd.1996).
Usually, by using nonopioid analgesic such as acetylsalicylic acid, choline magnesium trisalicylate, paracetamol, Ibuprofen BP/EP, fenoprofen, diflunisal (diflusinal) and Naproxen Base, or come pain management by using opium kind analgesics such as morphine, hydromorphone, methadone, levorphan, fentanyl, oxycodone and oxymorphone.
Include but not limited to 4-tetrazyl-4-Phenylpiperidine compound according to the compound of Formula I, the pain or the diarrhoea that can be used for preventing or treating animal,
Chemical formula (I)
Ar wherein 1For-C 3-C 8Cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; Ar 2Be phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; Z 1And Z 2Independently be-(C separately 1-C 4Alkyl) group; R 1For-(CH 2) nC (O) N (R 3) (R 4), R wherein 3And R 4Independent separately be H or-(C 1-C 4Alkyl); R 2For halogen ,-C 1-C 3Alkyl ,-O-(C 1-C 3Alkyl) ,-NH (C 1-C 3Alkyl) or-N (C 1-C 3Alkyl) 2N is the integer of 1-4; M is the integer of 0-4.In certain embodiments, the phenyl moiety that is connected to according to the piperidine ring 4-position of chemical formula i compound randomly is substituted with one or more R 2Group, wherein R 2Limit as above.
Compound (7) can be used for preventing or treating the exemplary 4-tetrazyl-4-Phenylpiperidine compound of pain and the diarrhoea of animal, has following structure:
Figure A20058000352200511
Compound (7)
(4-[4-(2-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-yl]-N, N-dimethyl-2,2-phenylbenzene-butyramide)
At the total U. S. application No.10/714 that is disclosed as US 2004/0152689A1 on November 13rd, 2003, on August 5th, 2004 that submits, disclose exemplary 4-tetrazyl-4-Phenylpiperidine compound, its synthetic method in 066 and be used to prevent and treat the pain of animal or the method for diarrhoea, this method comprises 4-tetrazyl-4-Phenylpiperidine compound of the animal of treatment of this kind of needs or preventive measures being used significant quantity, and this application content whole is incorporated this paper into by reference.
In addition, the method for preparing other 4-Phenylpiperidine compound has been described.People's such as Yaksh U.S. Patent No. 6,573 for example, 282B1 described Loperamide (4-(p-chloro-phenyl-)-4-hydroxy-n, N-dimethyl-α,, α-phenylbenzene-1-piperidines butyramide hydrochloric acid) synthetic.More specifically, patent ' 282 has been described dimethyl-(tetrahydrochysene-3,3-phenylbenzene-2-furylidene) brometo de amonio synthetic with and obtain 4-(p-chloro-phenyl-)-4-hydroxy-n, N-dimethyl-α with p-chloro-phenyl--4-piperidines alcohol condensation,, α-phenylbenzene-1-piperidines butyramide.Yet patent ' 282 is not described any the synthetic of tetrazolium compound partly that comprise.
Disclose about form the several different methods of tetrazyl from the nitrile substituting group.For example, Berstein et al.J.Synth.Org.Chem. (1987) 12:1133-34 has described by making the reaction of sodium azide in corresponding nitrile compound and the N-Methyl pyrrolidone form specific terazole derivatives in the presence of triethyl ammonium chloride, under 150 ℃ of temperature.
Demko et al. (2001) j.Org.Chem.66:7945-7850 report will be by containing nitrile molecule and sodiumazide and react in the presence of zinc bromide and the nitrile substituting group being converted into tetrazolium.Being reflected in the aqueous solution that Demko describes carried out.
Bold et al. (1998) J.Med.Chem.41:3387-3401 described by utilize methyl cellosolve as solvent, under refluxad will contain nitrile molecule and sodiumazide and in the presence of lithium chloride, react and nitrile is converted into corresponding tetrazolium.
The nitrile part that Moltzen et al. (1994) J.Med.Chem.37:4085-4099 has described the heterocycloalkenyl compound is converted into corresponding nitrile by under refluxad reacting with sodiumazide in THF, in the presence of the aluminum chloride.
Although in the document of being quoted, described the whole bag of tricks, but there is demand for the improvement preparation method who contains tetrazolyl compounds, even more specifically, for example according to the improvement preparation method's of the compound of Formula I demand, described compound includes but not limited to compound (7) for 4-tetrazyl-4-Phenylpiperidine compound in existence.
Any document of being quoted at the application's second joint is not to admit that described document is the application's a prior art.
Summary of the invention
In one embodiment, the present invention relates to the compound of chemical formula (2),
Figure A20058000352200521
It can be used for synthetic compound according to Formula I, such as but not limited to compound (7).
In another embodiment, the present invention relates to the compound of chemical formula (4),
Figure A20058000352200531
It can be used for synthetic compound according to Formula I, such as but not limited to compound (7).
In yet another embodiment, the present invention relates to the compound of chemical formula (9),
It can be used for synthetic compound according to Formula I, such as but not limited to compound (7).
In an embodiment again, the present invention relates to the compound of chemical formula (5),
It can be used for synthetic compound according to Formula I, such as but not limited to compound (7).
In another embodiment, the invention still further relates to a kind of composition, comprise sodiumazide, zinc salt, contain the solvent of polar proton inert solvent and the compound of chemical formula (2).
Figure A20058000352200541
In one embodiment, described solvent comprises the mixture of N-Methyl pyrrolidone and water.
In another embodiment, the present invention relates to a kind of composition, it can be used for compound (comprising for example compound (7)) synthetic according to Formula I, and described composition comprises polar proton inert solvent, non-nucleophilic base, according to the compound of chemical formula (2)
With the alkylating reagent that has according to the Formulae II structure
Figure A20058000352200543
Wherein n is the integer of 1-4; R 3And R 4Independent separately be H or-(C 1-C 4Alkyl); X 1For-Br ,-Cl or-I.
In yet another embodiment, the present invention relates to a kind of composition, it can be used for synthetic compound (comprising for example compound (7)) according to Formula I, and it comprises the compound of chemical formula (5)
Figure A20058000352200551
And the compound of chemical formula (6)
Figure A20058000352200552
In another embodiment, the present invention relates to a kind of composition, it can be used for synthetic compound (comprising for example compound (7)) according to Formula I, and described composition comprises the compound of sodiumazide, zinc salt and chemical formula (8).
Figure A20058000352200553
In yet another embodiment, the present invention relates to a kind of composition, it can be used for synthetic compound (comprising for example compound (7)) according to Formula I, and it comprises the compound of chemical formula (9)
Figure A20058000352200561
The compound of chemical formula (6)
And non-nucleophilic base.
In yet another embodiment, the compound that the present invention relates to chemical formula (14) is used for the purposes of synthetic compound according to Formula I such as but not limited to compound (7).
Figure A20058000352200563
In another embodiment, the present invention relates to the compound of chemical formula (15)
Or its salt, it can be used for synthetic compound according to Formula I such as but not limited to compound (7).
In yet another embodiment, the compound that the present invention relates to chemical formula (13) is used for the purposes of synthetic compound according to Formula I such as but not limited to compound (7).
In another embodiment, the compound or its salt that the present invention relates to chemical formula (18) is used for the purposes of synthetic compound according to Formula I such as but not limited to compound (7).
Figure A20058000352200573
In another embodiment, the present invention relates to the compound of chemical formula (20)
Or its salt, it can be used for synthetic compound according to Formula I such as but not limited to compound (7).
In another embodiment, the present invention relates to the compound of chemical formula (22)
Figure A20058000352200581
Or its salt, it can be used for synthetic compound according to Formula I such as but not limited to compound (7).
In another embodiment, the present invention relates to the compound of chemical formula (24)
Or its salt, it can be used for synthetic compound according to Formula I such as but not limited to compound (7).
In another embodiment, the present invention relates to the compound of chemical formula (25)
Figure A20058000352200591
Or its salt, it can be used for synthetic compound according to Formula I such as but not limited to compound (7).
In another embodiment, the present invention relates to the compound of chemical formula (26)
Figure A20058000352200592
Or its salt, it can be used for synthetic compound according to Formula I such as but not limited to compound (7).
In an embodiment again, the present invention relates to the preparation method of the compound of chemical formula (2),
It is included in the compound that makes chemical formula (1) in the solvent that contains polar proton inert solvent
Figure A20058000352200601
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided.
In another embodiment, the present invention relates to the preparation method of the compound of chemical formula (4),
Figure A20058000352200602
It comprises the compound that makes chemical formula (2)
Compound with Formula I X
Formula I X
Reaction, so that the compound of chemical formula (4) to be provided, wherein X is a halogen, such as but not limited to Br and Cl.
In yet another embodiment, the present invention relates to the preparation method of compound (7),
Be included in the compound that makes chemical formula (5) in the solvent that contains polar proton inert solvent
Figure A20058000352200612
Compound with chemical formula (6)
Figure A20058000352200613
Reaction in the presence of non-nucleophilic base.
In another embodiment, the present invention relates to the preparation method of compound (7),
Comprise:
(a) make the compound of chemical formula (4)
Debenzylation in the presence of hydrogen and noble metal catalyst is to provide the compound of chemical formula (5);
With
(b) make the compound of chemical formula (5) and the compound of chemical formula (6)
In the presence of non-nucleophilic base, react, form the compound of chemical formula (7) thus.
Figure A20058000352200631
In another embodiment, the present invention relates to the preparation method of compound (7),
Figure A20058000352200632
Be included in the solvent that comprises polar proton inert solvent, make the compound of chemical formula (2)
Figure A20058000352200633
Compound with Formula I X
Formula I X
Reaction in the presence of non-nucleophilic base, so that the compound of chemical formula (4) to be provided, wherein, X is a halogen, such as but not limited to Br and Cl;
Make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided
Figure A20058000352200642
And the compound that makes chemical formula (5) subsequently is converted into compound (7).
In yet another embodiment, the present invention relates to the preparation method of compound (7),
Figure A20058000352200643
Be included in the solvent that comprises polar proton inert solvent, make the compound of chemical formula (2)
Compound with Formula I X
Figure A20058000352200652
Formula I X
Reaction in the presence of non-nucleophilic base, wherein, X is a halogen, such as but not limited to Br and Cl, so that the compound of chemical formula (4) to be provided
Figure A20058000352200653
Make chemical formula (4) compound be converted into compound (7) subsequently.
The present invention also relates to the preparation method of compound (7) in another embodiment,
Comprise that (a) makes the compound of chemical formula (1)
Figure A20058000352200661
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided
Figure A20058000352200662
(b) make the compound of chemical formula (2) be converted into compound (7).
In another embodiment, the present invention relates to the preparation method of compound (7),
Figure A20058000352200663
Comprising that (a) makes the compound of chemical formula (1)
Figure A20058000352200664
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided
Figure A20058000352200671
Use the compound of Formula I X subsequently
Figure A20058000352200672
Formula I X
With its alkylation, wherein X is a halogen in the presence of non-nucleophilic base, such as but not limited to Br and Cl, and so that the compound of chemical formula (4) to be provided,
Subsequently, make its debenzylation in the presence of hydrogen and noble metal catalyst, so that the compound of chemical formula (5) to be provided
In the presence of non-nucleophilic base, make the compound reaction of itself and chemical formula (6),
Figure A20058000352200681
So that compound (7) to be provided
In another embodiment, the present invention relates to the preparation method of compound (7),
Comprise that (a) in comprising the solvent of polar proton inert solvent, makes the compound of chemical formula (8)
Figure A20058000352200684
With sodiumazide at zinc salt such as but not limited to Zn (Br) 2There is reaction down, so that the compound of chemical formula (9) to be provided
(b) make the compound of chemical formula (9) be converted into compound (7).
In certain embodiments, polar proton inert solvent is selected from two  alkane, N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) and combination thereof.In other embodiments, solvent comprises the suitable polar proton inert solvent and the mixture of water.In these embodiments, the ratio of water and polar proton inert solvent can be about 10: about 1: 1 (water: in scope polar proton inert solvent) of 1-.In certain embodiments, polar proton inert solvent is two  alkane.
In another embodiment, the present invention relates to the preparation method of compound (7),
Figure A20058000352200692
Comprise that (a) in comprising the solvent of polar proton inert solvent, makes the compound of chemical formula (9)
Figure A20058000352200693
With the compound of chemical formula (6)
Figure A20058000352200701
Reaction in the presence of non-nucleophilic base is to provide the compound of chemical formula (10)
(b) make the compound of chemical formula (10) be converted into compound (7).
In another embodiment, the present invention relates to the preparation method of compound (7),
Comprise that (a) in comprising the solvent of polar proton inert solvent, makes the compound of chemical formula (8)
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (9) to be provided
Figure A20058000352200711
(b) make the compound of chemical formula (9) and the compound of chemical formula (6)
Figure A20058000352200712
Reaction in the presence of non-nucleophilic base is to provide the compound of chemical formula (10)
Figure A20058000352200713
(c) utilize the compound of Formula I X to make the alkylation of chemical formula (10),
Figure A20058000352200714
Formula I X
Wherein, X is a halogen, such as but not limited to Br and Cl, so that compound (7) to be provided
In certain embodiments, polar proton inert solvent is selected from two  alkane, N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) and combination thereof.In other embodiments, solvent comprises the suitable polar proton inert solvent and the mixture of water.In these embodiments, the ratio of water and polar proton inert solvent can be about 10: about 1: 1 (water: in scope polar proton inert solvent) of 1-.In certain embodiments, polar proton inert solvent is two  alkane.
In an embodiment again, the present invention relates to the preparation method of compound (7),
Figure A20058000352200722
Comprise: the compound that (a) makes chemical formula (2)
Figure A20058000352200723
React in the presence of non-nucleophilic base with the compound of Formula I X,
Formula I X
Wherein, X is a halogen, such as but not limited to Br and Cl, so that the compound of chemical formula (4) to be provided
(b) make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided
Figure A20058000352200733
(c) compound of chemical formula (5) and the compound of chemical formula (6) are reacted in the presence of non-nucleophilic base,
Figure A20058000352200734
Form compound (7) thus
Figure A20058000352200741
In yet another embodiment, the present invention relates to the preparation method of compound (7),
Comprise that (a) makes the compound of chemical formula (10)
Figure A20058000352200743
With the compound reaction of Formula I X,
Formula I X
Wherein, X is a halogen, such as but not limited to Br and Cl, forms compound (7) thus
In another embodiment, the present invention relates to the preparation method of compound (7),
Comprise: the compound that (a) makes chemical formula (9)
Figure A20058000352200753
React in the presence of non-nucleophilic base with the compound of chemical formula (6),
So that the compound of chemical formula (10) to be provided
Figure A20058000352200761
(b) compound of chemical formula (10) and the compound of Formula I X are reacted,
Formula I X
Wherein, X is a halogen, such as but not limited to Br and Cl, forms compound (7) thus.
In yet another embodiment, the present invention relates to the preparation method of the compound of chemical formula (5)
Figure A20058000352200763
Comprise:
(a) make the compound of chemical formula (2)
React in the presence of non-nucleophilic base with the compound of Formula I X,
Figure A20058000352200771
Formula I X
Wherein, X is a halogen, such as but not limited to Br and Cl, so that the compound of chemical formula (4) to be provided
Figure A20058000352200772
Subsequently, make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided.
In yet another embodiment, the present invention relates to preparation method according to the compound of chemical formula (5)
Figure A20058000352200773
Comprise: the compound that (a) makes chemical formula (1)
Figure A20058000352200774
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided
The compound of chemical formula (2) and the compound of Formula I X are reacted in the presence of non-nucleophilic base
Formula I X
Wherein, X is a halogen, such as but not limited to Br and Cl, so that the compound of chemical formula (4) to be provided
Figure A20058000352200783
Subsequently, make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided.
In another embodiment, the present invention relates to preparation method according to the compound of chemical formula (9),
Figure A20058000352200784
Comprise the compound debenzylation in the presence of hydrogen and noble metal catalyst that makes chemical formula (2),
Figure A20058000352200791
So that the compound of chemical formula (9) to be provided.
In yet another embodiment, the present invention relates to preparation method according to the compound of chemical formula (9),
Figure A20058000352200792
Be included in the solvent that comprises polar proton inert solvent, the compound of chemical formula (1) and sodiumazide reacted in the presence of zinc salt,
Figure A20058000352200793
So that the compound of chemical formula (2) to be provided,
Figure A20058000352200794
And make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (2), so that the compound of chemical formula (9) to be provided.
In yet another embodiment, the present invention relates to preparation method according to the compound of chemical formula (9),
Be included in the solvent that comprises polar proton inert solvent, the compound of chemical formula (8) and sodiumazide reacted in the presence of zinc salt,
Figure A20058000352200802
The compound of chemical formula (9) is provided thus.Aspect of this embodiment, described solvent comprises the mixture of two  alkane and water.
In another embodiment, the present invention relates to the preparation method of the compound of chemical formula (4),
Comprise the compound that makes chemical formula (1)
Figure A20058000352200804
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided
And in comprising the solvent of polar proton inert solvent, the compound of chemical formula (2) and the compound of Formula I X are reacted in the presence of non-nucleophilic base,
Formula I X
Wherein, X is selected from Br, Cl or I, to produce compound (4).
In another embodiment, the present invention relates to the preparation method of the compound of chemical formula (5),
Comprise the compound debenzylation in the presence of hydrogen and noble metal catalyst that makes chemical formula (4),
So that the compound of chemical formula (5) to be provided.
In another embodiment, the present invention relates to the compound or its salt of chemical formula (20), it can be used for synthesizing
According to the compound of Formula I such as but not limited to compound (7).
Figure A20058000352200821
In yet another embodiment, the present invention relates to the compound or its salt of chemical formula (25).It can be used for synthetic compound according to Formula I such as but not limited to compound (7).
Figure A20058000352200822
In another embodiment, the present invention relates to chemical formula XII or its salt,
Figure A20058000352200823
Wherein, R 5Be selected from
Described compound can be used for synthetic compound according to Formula I, such as but not limited to compound (7).
In yet another embodiment, the present invention relates to the compound of chemical formula XIV
Or its salt, wherein, n is the integer of 1-4, R 3And R 4Independent separately be H or-(C 1-C 4And R alkyl), 5Be selected from
Figure A20058000352200832
Described compound can be used for synthetic compound according to Formula I, such as but not limited to compound (7).In aspect this embodiment concrete, in the compound of chemical formula XIV, n is 1, R 3And R 4Be hydrogen, R 5Be
In aspect another of this embodiment is concrete, in the compound of chemical formula XIV, n is 1, R 3And R 4Be hydrogen, R 5Be
Figure A20058000352200834
In yet another embodiment, the present invention relates to the preparation method of the compound of chemical formula (15),
Comprise the compound that makes chemical formula (14)
Compound with Formula I X Reaction in the presence of non-nucleophilic base, to produce compound (15), wherein X is selected from Br, Cl or I.
In another embodiment, the present invention relates to the preparation method of the compound of chemical formula (15), comprise making compound (20)
Figure A20058000352200843
With compound (21)
Figure A20058000352200844
Reaction is to generate the compound of chemical formula (22)
Figure A20058000352200845
In ethanol, make compound (22) have down protection, so that the compound of chemical formula (14) to be provided at potassium formiate and Pd/C
Figure A20058000352200851
Make the compound of chemical formula (14) and the compound of Formula I X Reaction in the presence of non-nucleophilic base,
Wherein, X is selected from Br, Cl or I, to generate compound (15).
In another embodiment, the invention still further relates to the preparation method of the compound of chemical formula (15), comprise the compound that makes chemical formula (8)
Figure A20058000352200853
React in the presence of zinc salt with sodiumazide, with the compound of generation chemical formula (9),
Make the compound reaction of the compound and the chemical formula (12) of chemical formula (9),
Figure A20058000352200855
With the compound of generation chemical formula (14),
Figure A20058000352200861
The compound of chemical formula (14) and the compound of Formula I X are reacted in the presence of non-nucleophilic base
Figure A20058000352200862
Wherein, X is selected from Br, Cl or I, to generate compound (15).
In another embodiment, the present invention relates to the preparation method of the compound of chemical formula (26),
Figure A20058000352200863
Comprise the compound that makes chemical formula (25)
Figure A20058000352200864
React in the presence of non-nucleophilic base with the compound of Formula I X,
Wherein, X is selected from Br, Cl or I, to generate compound (26).
In another embodiment, the present invention relates to the preparation method of the compound of chemical formula (26),
Figure A20058000352200871
Comprise the compound that makes chemical formula (20)
Figure A20058000352200872
Compound reaction with chemical formula (23)
Figure A20058000352200873
To generate the compound of chemical formula (24)
Figure A20058000352200881
In ethanol, make compound (24) have down protection, so that the compound of chemical formula (25) to be provided at potassium formiate and Pd/C
Figure A20058000352200882
The compound of chemical formula (25) and the compound of Formula I X are reacted in the presence of non-nucleophilic base,
Wherein, X is selected from Br, Cl or I, to generate compound (26).
In yet another embodiment, the present invention relates to the preparation method of the compound of chemical formula (20), comprise the compound that makes chemical formula (18)
With the compound reaction of chemical formula (19),
Figure A20058000352200885
To generate the compound of chemical formula (20).
In yet another embodiment, the present invention relates to the preparation method of the compound of chemical formula (20), comprise the compound that makes chemical formula (17)
Figure A20058000352200891
In the presence of zinc salt, react so that the compound of chemical formula (18) to be provided with sodiumazide,
Figure A20058000352200892
Make the compound reaction of the compound and the chemical formula (19) of chemical formula (18),
Figure A20058000352200893
To generate the compound of chemical formula (20).
In another embodiment, the present invention relates to the preparation method of the compound of chemical formula (25),
Figure A20058000352200894
Comprise the compound that makes chemical formula (20)
Figure A20058000352200895
With the compound reaction of chemical formula (23),
Figure A20058000352200901
To generate the compound of chemical formula (24)
In ethanol, make the compound of chemical formula (24) have down protection, to produce the compound of chemical formula (25) at potassium formiate and Pd/C.
In yet another embodiment, the present invention relates to the preparation method of compound (7),
Comprise that the compound that makes chemical formula (15) goes protection,
With the compound of generation chemical formula (5),
Figure A20058000352200911
Make the compound of chemical formula (5) be converted into compound (7).
In another embodiment, the present invention relates to the preparation method of compound (7),
Figure A20058000352200912
Comprise that the compound that makes chemical formula (26) goes protection,
Figure A20058000352200913
With the compound of generation chemical formula (5),
Make the compound of chemical formula (5) be converted into compound (7).
In an embodiment again, the present invention relates to the preparation method of compound (7),
Comprise the compound that makes chemical formula (14)
React in the presence of non-nucleophilic base with the compound of Formula I X,
Wherein, X is selected from Br, Cl or I, with generation compound (15),
Figure A20058000352200924
Make the compound of chemical formula (15) be converted into compound (7).
In yet another embodiment, the present invention relates to the preparation method of compound (7),
Comprise the compound that makes chemical formula (25)
React in the presence of non-nucleophilic base with the compound of Formula I X,
Wherein, X is selected from Br, Cl or I, with generation compound (26),
Figure A20058000352200934
Make the compound of chemical formula (26) be converted into compound (7).
In another embodiment, the present invention relates to the preparation method of compound (7),
Figure A20058000352200941
Comprise that the compound that makes chemical formula (22) goes protection
With the compound of generation chemical formula (14),
Figure A20058000352200943
The compound of chemical formula (14) and the compound of Formula I X are reacted in the presence of non-nucleophilic base,
Figure A20058000352200944
Wherein, X is selected from Br, Cl or I, with generation compound (15),
Figure A20058000352200951
Make the compound of chemical formula (15) be converted into compound (7).
In yet another embodiment, the present invention relates to the preparation method of compound (7),
Figure A20058000352200952
Comprise that the compound that makes chemical formula (24) goes protection
Figure A20058000352200953
With the compound of generation chemical formula (25),
Figure A20058000352200961
The compound of chemical formula (25) and the compound of Formula I X are reacted in the presence of non-nucleophilic base,
Figure A20058000352200962
Wherein, X is selected from Br, Cl or I, with generation compound (26),
Figure A20058000352200963
Make the compound of chemical formula (26) be converted into compound (7).
In an embodiment again, the present invention relates to the preparation method of compound (7),
Figure A20058000352200964
Comprise the compound that makes chemical formula (20)
With the compound reaction of chemical formula (21),
Figure A20058000352200972
With the compound of generation chemical formula (22),
Figure A20058000352200973
In ethanol, make the compound of chemical formula (22) have down protection, so that the compound of chemical formula (14) to be provided at potassium formiate and Pd/C
Figure A20058000352200974
The compound of chemical formula (14) and the compound of Formula I X are reacted in the presence of non-nucleophilic base,
Figure A20058000352200981
Wherein, X is selected from Br, Cl or I, with the compound of generation chemical formula (15),
Figure A20058000352200982
Make the compound of chemical formula (15) be converted into compound (7).
In an embodiment again, the present invention relates to the preparation method of compound (7),
Comprise the compound that makes chemical formula (20)
Figure A20058000352200984
With the compound reaction of chemical formula (23),
Figure A20058000352200991
With the compound of generation chemical formula (24),
In ethanol, make compound (24) have down protection, so that the compound of chemical formula (25) to be provided at potassium formiate and Pd/C
The compound of chemical formula (25) and the compound of Formula I X are reacted in the presence of non-nucleophilic base,
Wherein, X is selected from Br, Cl or I, to generate compound (26)
Make the compound of chemical formula (26) be converted into compound (7).
In another embodiment, the present invention relates to the preparation method of compound (7),
Comprise the compound that makes chemical formula (9)
Figure A20058000352201003
With the compound reaction of chemical formula (12),
Figure A20058000352201004
With the compound of generation chemical formula (14),
The compound of chemical formula (14) and the compound of Formula I X are reacted in the presence of non-nucleophilic base,
Wherein, X is selected from Br, Cl or I, with the compound of generation chemical formula (15),
Make the compound of chemical formula (15) be converted into compound (7).
In yet another embodiment, the present invention relates to the preparation method of compound (7),
Comprise the compound that makes chemical formula (9)
With the compound reaction of chemical formula (28),
With the compound of generation chemical formula (25),
Figure A20058000352201023
The compound of chemical formula (25) and the compound of Formula I X are reacted in the presence of non-nucleophilic base,
Wherein, X is selected from Br, Cl or I, to generate the compound of chemical formula (26)
Make the compound of chemical formula (26) be converted into compound (7).
In another embodiment, the present invention relates to the compound of chemical formula (35)
Figure A20058000352201031
Or its salt, it can be used for synthetic compound according to Formula I, such as but not limited to compound (7).
In another embodiment, the present invention relates to the compound of chemical formula (36)
Figure A20058000352201032
Or its salt, it can be used for synthetic compound according to Formula I, such as but not limited to compound (7).
In another embodiment, the present invention relates to the method for synthetic compound (7),
Comprise the compound that makes chemical formula (20)
With the compound reaction of chemical formula (35),
With the compound of generation chemical formula (36),
Figure A20058000352201043
In ethanol, make the compound of chemical formula (36) have down protection at potassium formiate and Pd/C, so that the compound of chemical formula (10) to be provided,
Figure A20058000352201051
Be converted into compound (7) with the compound that makes chemical formula (10).
The present invention can be by being understood described embodiment exemplary illustration non-limiting embodiments of the present invention with reference to following detailed description and exemplary embodiment more fully.
4. embodiment
4.1. definition
As used herein, generic term " 4-tetrazyl-4-Phenylpiperidine compound " is meant the compound with Formula I structure,
Figure A20058000352201052
Chemical formula (I)
Wherein, Ar 1For-C 3-C 8Cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces;
Ar 2Be phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces;
Z 1And Z 2Independently be-(C separately 1-C 4Alkyl) group;
R 1For-(CH 2) nC (O) N (R 3) (R 4);
R 3And R 4Independent separately be H or-(C 1-C 4Alkyl);
R 2For halogen ,-C 1-C 3Alkyl ,-O-(C 1-C 3Alkyl) ,-NH (C 1-C 3Alkyl) or-N (C 1-C 3Alkyl) 2
N is the integer of 1-4; And
M is the integer of 0-4.
In certain embodiments, be connected to choose wantonly and be substituted with one or more R according to the phenyl moiety of the piperidine ring 4-position of chemical formula i compound 2Group, wherein R 2Limit as above.
Term " halogenide " is meant fluorochemical, muriate, bromide or iodide.
Term " halogen " is meant-F ,-Cl ,-Br or-I.
Term " (C 1-C 3) alkyl " be meant saturated straight chain or branched hydrocarbon with 1-3 carbon atom.Representational saturated straight chain-(C 1-C 3) alkyl is methyl, ethyl and n-propyl, and saturated side chain-(C 1-C 3) alkyl is sec.-propyl.
Term " (C 1-C 4) alkyl " be meant saturated straight chain or branched hydrocarbon with 1-4 carbon atom.Representational saturated straight chain-(C 1-C 4) alkyl is methyl, ethyl, n-propyl and normal-butyl.Representational saturated side chain-(C 1-C 4) alkyl is sec.-propyl, sec-butyl, isobutyl-and the tertiary butyl.
The compound of related herein concrete chemical formula also is used for comprising the salt form of this compound." salt " of compound disclosed herein is meant by acid and 4-tetrazyl-4-Phenylpiperidine compound or can be used for the formed salt of alkaline nitrogenous base of its synthetic intermediate.Exemplary salt includes but not limited to: sulfamate, vitriol, Citrate trianion, acetate, oxalate, muriate, bromide, iodide, nitrate, hydrosulfate, phosphoric acid salt, acid phosphate, Yi Yansuan salt, lactic acid salt, salicylate, the acid Citrate trianion, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate salt, succinate, maleate, gentisate (gentisinate), fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutaminate, mesylate, esilate, benzene sulfonate, right-tosylate and two hydroxyl salicylates (promptly 1,1 '-methylene radical-two-(2-hydroxyl-3-naphthoate)).Salt and inorganic or organic bases that term " salt " also refers to have the 4-tetrazyl-4-Phenylpiperidine compound of acidic functionality such as carboxylic acid functional or can be used for its synthetic intermediate.Exemplary alkali includes but not limited to: the oxyhydroxide of basic metal such as sodium, potassium and lithium; The oxyhydroxide of alkaline-earth metal such as calcium and magnesium; The oxyhydroxide of other metal such as aluminum and zinc; Ammonia; And organic amine, as one, two or the trialkylamine that do not replace or hydroxyl replaces; Dicyclohexyl amine; Tributylamine; Pyridine; N-methyl-N-ethamine; Diethylamine; Triethylamine; Single-, two-or three-(2-hydroxy lower alkyl amine), as single-, two-or three-(2-hydroxyethyl) amine, 2-hydroxyl-tert-butylamine or three-(methylol) methylamine; N, N-two low alkyl groups-N-(hydroxy lower alkyl)-amine, as N, N-dimethyl-N-(2-hydroxyethyl) amine or three-(2-hydroxyethyl) amine; N-methyl D-glycosamine; With amino acid such as arginine, Methionin etc.
4.2.4-the preparation method of tetrazyl-4-Phenylpiperidine compound
4.2.1. compound (2) (1-phenmethyl-4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines) is synthetic
In one embodiment, the present invention relates to prepare the method for compound (2) (1-phenmethyl-4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines), comprise make compound (1) (1-phenmethyl-4-cyano group-4-Phenylpiperidine) (commercially available) and sodiumazide at zinc salt such as but not limited to zinc halide (ZnBr for example 2, ZnCl 2And ZnI 2) or other suitable zinc salt such as Zn (ClO 4) 2Or Zn (CF 3SO 3) 2There is reaction down, shown in following scheme 1:
Scheme 1
Figure A20058000352201071
1-phenmethyl-4-cyano group-4-Phenylpiperidine 1-phenmethyl-4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines
In some optional embodiment, the phenyl moiety that is connected on the piperidine ring 4-position of compound (1) is substituted with one or more R 2Group, wherein R 2Group definition as above.
The reaction of scheme 1 is preferably carried out in comprising the solvent of polar proton inert solvent.The example of suitable polar proton inert solvent that can be used for the reaction of scheme 1 includes but not limited to N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO).In certain embodiments, solvent is N-Methyl pyrrolidone or N,N-DIMETHYLACETAMIDE.In specific embodiments, solvent is a N-Methyl pyrrolidone.
In certain embodiments, the solvent that is used for the reaction of scheme 1 is the suitable polar proton inert solvent and the mixture of water.In this embodiment, the ratio of polar proton inert solvent and water can be about 50: about 2: 1 (v/v) (polar proton inert solvents: water) of 1-; About 20: about 4: 1 (polar proton inert solvents: water) of 1-; Or about 15: about 10: 1 (polar proton inert solvents: water) of 1-.In specific embodiments, described solvent mixture is a N-Methyl pyrrolidone: water.
In certain embodiments, the reaction of scheme 1 is used with respect to the zinc salt of compound (1) original bulk for about 5 molar equivalents of about 1-or about 4 molar equivalents of about 2-and is carried out.In yet another embodiment, the reaction of scheme 1 is used and is carried out for the zinc salt of about 3 molar equivalents with respect to compound (1).Described zinc salt can be selected from and comprise ZnBr 2, ZnCl 2And ZnI 2Zinc halide and other suitable zinc salt such as Zn (ClO arbitrarily 4) 2Or Zn (CF 3SO 3) 2In specific embodiments, zinc halide is ZnBr 2Zinc salt can be from for example Aldrich Chemical Co., Milwaukee, and Wisconsin buys.
In certain embodiments, the reaction of scheme 1 is used with respect to the sodiumazide of compound (1) original bulk for about 5 molar equivalents of about 1-or about 4 molar equivalents of about 2-and is carried out.In specific embodiments, the reaction of scheme 1 is used and is carried out for the sodiumazide of about 4 molar equivalents with respect to compound (1).
In certain embodiments, compound (1) is provided as salt, hydrochloride for example, it can utilize methods known in the art, with reaction of sodium azide before be converted into unhindered amina.For example, the hydrochloride of compound (1) is dissolved in suitable organic solvent such as but not limited in the chloroform, and so that solution to be provided, this soln using is Na for example 2CO 3Saturated aqueous solution extraction.Reclaim organic layer and utilize the organic solvent reextraction water layer of additional volumes.Merge organic solvent layer, the water extraction, drying is evaporated so that the compound as unhindered amina (1) to be provided subsequently for example through anhydrous sodium sulfate drying.
The reaction of scheme 1 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.In certain embodiments, being reflected in the inert atmosphere of scheme 1 carried out.Of this embodiment non-limiting aspect, being reflected under the nitrogen atmosphere of scheme 1 carried out.Another of this embodiment non-limiting aspect, being reflected under the argon atmospher of scheme 1 carried out.
In certain embodiments, being reflected under about 100 ℃-Yue 200 ℃ of temperature, about 120 ℃-Yue 150 ℃ of temperature or the about 130 ℃-Yue 140 ℃ of temperature of scheme 1 carried out.
The process of scheme 1 reaction can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.In one embodiment, proceed to initiator according to the reaction of scheme 1 and run out, perhaps in another embodiment, remain unchanged substantially until the ratio of product compound (2) with initiator compound (1).
In certain embodiments, the reaction of scheme 1 utilizes the solution of compound (1) to carry out, and wherein the initial concentration of compound (1) is about 1.0M of about 0.05M-or the about 0.5M of about 0.1M-.In specific embodiments, the initial concentration of compound (1) is about 0.25M in the reaction of scheme 1.
The compound that forms in the reaction of scheme 1 (2) can utilize methods known in the art, reagent and equipment to emanate and/or purifying, includes but not limited to that following 5.1 joints are disclosed.
4.2.2. the compound of Formulae II I is synthetic
In another embodiment, the present invention relates to the preparation method of compound (for example compound (4)) according to Formulae II I, being included in non-nucleophilic base exists down, make compound (2) (1-phenmethyl-4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines) with according to the reaction of the alkylating reagent of Formulae II, shown in following scheme 2:
Scheme 2
Wherein, n is the integer of 1-4, R 3And R 4Independent separately be H or-(C 1-C 4And X alkyl), 1For-Br ,-Cl or-I.In certain embodiments, be connected compound (2) and randomly be substituted with one or more R by the phenyl moiety on the 4-position of the piperidine ring of the compound of the Formulae II I of its generation 2Group, wherein R 2Definition as above.
The reaction of scheme 2 is preferably carried out in comprising the solvent of polar proton inert solvent.The example of suitable polar proton inert solvent that can be used for the reaction of scheme 2 includes but not limited to N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO).In certain embodiments, solvent is dimethyl formamide or N,N-DIMETHYLACETAMIDE.In specific embodiments, solvent is a dimethyl formamide.
In certain embodiments, the starting point concentration of compound (2) in the reaction of scheme 2 is about 0.8M of about 0.1M-or the about 0.6M of about 0.2M-.In specific embodiments, the starting point concentration of compound (2) in the reaction of scheme 2 is about 0.4M.
The reaction of scheme 2 can be carried out in the presence of the alkali of any appropriate, such as but not limited to triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or 2,3,4,6,7,8,9,10-octahydro-Mi Dingbing [1,2-α] azepine (DBU).In certain embodiments, non-nucleophilic base is triethylamine, yellow soda ash or salt of wormwood.In certain embodiments, the level that exists in the reaction of scheme 2 of non-nucleophilic base is for respect to about 0.5 molar equivalent-Yue 3.0 molar equivalents of compound (2) starting point concentration, about 0.75 molar equivalent-Yue 2.0 molar equivalents or about 1.0 molar equivalents-Yue 1.5 molar equivalents.In specific embodiments, non-nucleophilic base is a salt of wormwood.In specific embodiments, the reaction utilization of scheme 2 is carried out with respect to the non-nucleophilic base of about 1 molar equivalent of compound (2) starting point concentration.
In certain embodiments, utilize alkylating reagent to carry out the reaction of scheme 2, the level that this alkylating reagent exists is about 0.80 molar equivalent-Yue 1.5 molar equivalents, about 0.85 molar equivalent-Yue 1.2 molar equivalents or about 0.95 molar equivalent-1.1 molar equivalent with respect to the compound that exists in the reaction according to scheme 2 (2) original bulk.In specific embodiments, the reaction utilization of scheme 2 is carried out with respect to the alkylating reagent of about 1 molar equivalent of the compound that exists in the reaction according to scheme 2 (2) original bulk.Comprise that the alkylating reagent according to any appropriate of the compound of Formulae II all can be used for the reaction of scheme 2, this reaction will provide the expectation product according to Formulae II I.In certain embodiments, be the haloalkyl acid amides according to the alkylating reagent of Formulae II, such as but not limited to bromoacetamide, chlor(o)acetamide or iodo-acid amide.In other non-limiting embodiments, alkylating reagent is an acrylamide.In certain embodiments, the alkylating reagent according to Formulae II is bromoacetamide or chlor(o)acetamide.In specific embodiments, be bromoacetamide (compound (3)) according to the alkylating reagent of Formulae II, and in another particular, be chlor(o)acetamide (compound (11)) according to the alkylating reagent of Formulae II.
Figure A20058000352201111
In certain embodiments, alkylated reaction carries out in the presence of the iodide of catalytic amount.These iodide on the one hand that are used for scheme 2 reactions can metal-salt (MI p) form add, wherein M is I family or II family metal.P=1, then M is an I family metal, p=2, then M is an II family metal.In certain embodiments, iodide are provided as LiI, NaI, KI, CsI, CaI 2, MgI 2Or SrI 2Salt.In certain embodiments, the iodide salt that can be used in scheme 2 reactions comprises potassiumiodide, sodium iodide, lithium iodide and cesium iodide and tetra-allkylammonium iodide.In certain embodiments, iodide salt is NaI or KI.When using, the initial level that is present in the iodide salt in scheme 2 reactions is about 0.01 molar equivalent-Yue 2.0 molar equivalents, about 0.05 molar equivalent-Yue 1.0 molar equivalents, about 0.1 molar equivalent-Yue 0.6 molar equivalent or about 0.1 molar equivalent-Yue 0.25 molar equivalent with respect to the original bulk of compound (2).
In each embodiment, being reflected under about 25 ℃-Yue 100 ℃ of temperature, about 30 ℃-Yue 80 ℃ of temperature or the about 40 ℃-Yue 60 ℃ of temperature of scheme 2 carried out.
The sufficiently long time is carried out in the reaction of scheme 2, so that compound (2) is converted into the compound of Formulae II I.In one embodiment, proceed to that initiator (for example compound (2)) exhausts or in another embodiment according to the reaction of scheme 2, the ratio that reaction proceeds to product (according to the compound of Formulae II I) and initiator (compound (2)) remains unchanged substantially.Usually, the time that is enough to the scheme of finishing 2 reaction is about 4 hours-Yue 48 hours, about 8 hours-Yue 36 hours or about 12 hours-Yue 24 hours.In specific embodiments, carried out about 16 hours according to the reaction of scheme 2.
The reaction of scheme 2 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.In certain embodiments, being reflected in the inert atmosphere of scheme 2 carried out.Of this embodiment non-limiting aspect, being reflected under the nitrogen atmosphere of scheme 2 carried out.Another of this embodiment non-limiting aspect, being reflected under the argon atmospher of scheme 2 carried out.
The process of scheme 2 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC "), nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.
Compound according to scheme 2 synthetic Formulae II I can utilize methods known in the art, reagent and equipment to emanate and/or purifying, includes but not limited to that following 5.2 joints are disclosed.
4.2.3. the compound of Formula I V is synthetic
In another embodiment, the present invention relates to the preparation method of compound (for example compound (5)), comprise making the step of taking off the N-benzyl according to the compound of Formulae II I according to Formula I V, shown in the following scheme 3:
Scheme 3
Figure A20058000352201121
Wherein, n is the integer of 1-4, R 3And R 4Independent separately be H or-(C 1-C 4Alkyl).In certain embodiments, be connected the compound of Formulae II I and be substituted with one or more R by the phenyl moiety on the 4-position of the piperidine ring of the compound of the Formula I V of its generation 2Group, wherein R 2Definition as above.
The reaction of scheme 3 is preferably carried out in containing the solvent of polar proton inert solvent.The example that can be used for the suitable polar proton inert solvent in the reaction of scheme 3 includes but not limited to lower alkanols alcohol, as methyl alcohol, ethanol, Virahol, n-propyl alcohol, butanols and ethylene glycol.In certain embodiments, solvent is methyl alcohol or ethanol.In specific embodiments, polar proton inert solvent is an ethanol.
In the reaction of scheme 3, the starting point concentration of the compound of the Formulae II I of existence is the about 0.8M of about 0.025M-, the about 0.4M of about 0.05M-or the about 0.2M of about 0.1M-.
In certain embodiments, the reaction of scheme 3 is also carried out in the presence of such as but not limited to methylsulfonic acid, toluenesulphonic acids, hydrochloric acid, sulfuric acid, phosphoric acid, acetate or camphorsulfonic acid at suitable acid catalyst.In certain embodiments, acid catalyst is hydrochloric acid or acetate.In specific embodiments, described acid catalyst is an acetate.
In certain embodiments, the initial level of acid catalyst that is used for the reaction of scheme 3 is about 0.01 molar equivalent-Yue 0.5 molar equivalent or about 0.05 molar equivalent-Yue 0.25 molar equivalent with respect to the compound of Formulae II I.In specific embodiments, the initial level of acid catalyst that is used for the reaction of scheme 3 is about 0.1 molar equivalent with respect to the compound of Formulae II I.
The N-benzyl reaction of going of scheme 3 can be to carry out in the presence of the platinum metal catalysts at hydrogen and precious metal.Suitable noble metal catalyst is known in the art, and includes but not limited to comprise those of iridium, osmium, palladium, platinum, rhodium or ruthenium.This catalyzer generally comprises the precious metal that is distributed on the suitable carrier, and described carrier is such as but not limited to activated carbon.In certain embodiments, catalyzer comprises palladium, platinum, rhodium or ruthenium.In other embodiments, catalyzer comprises palladium or platinum.In specific embodiments, catalyzer comprises the Powdered palladium that is distributed on the activity carbon carrier.
In certain embodiments, the compound according to Formulae II I is dissolved in the polar proton inert solvent such as but not limited under the argon atmospher at inert atmosphere.In this embodiment on the other hand, contain the container that comprises according to the reaction mixture of the solution of compound, acid catalyst and the noble metal catalyst of Formulae II I with hydrogen purge.The hydrogen that is reflected at according to scheme 3 is existed down, at about normal pressure (about 14.7psi (pound/square inch))-Yue 500psi, carry out at about normal pressure (about 14.7psi)-Yue 100psi or under the pressure of about normal pressure (about 14.7psi)-Yue 25psi.
In certain embodiments, according to about 5 ℃-Yue 100 ℃ of being reflected at of scheme 3, at about 15 ℃-Yue 50 ℃ or under about 20 ℃-Yue 30 ℃ temperature, carry out.
The sufficiently long time is carried out in the reaction of scheme 3 so that the compound of Formulae II I is converted into the compound of Formula I V.In one embodiment, the reaction of scheme 3 proceeds to that initiator (compound of Formulae II I) exhausts or in another embodiment, and the ratio that reaction proceeds to product (according to the compound of Formula I V) and initiator (compound of Formulae II I) remains unchanged substantially.Usually, the time that is enough to the scheme of finishing 3 reaction is about 4 hours-Yue 48 hours, about 8 hours-Yue 36 hours or about 12 hours-Yue 24 hours.In specific embodiments, the reaction of scheme 3 was carried out about 16 hours.
The process of scheme 3 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.
Compound according to scheme 3 synthetic Formula I V can utilize methods known in the art, reagent and equipment to emanate and/or purifying, includes but not limited to that following 5.3 joints are disclosed.
4.2.4. preparation method according to the compound of chemical formula VII
Scheme 4 illustrates the preparation method according to the compound of chemical formula VII (for example compound (6)).In certain embodiments, utilize thionyl chloride will be converted into the bromacyl chloride (J.S.Pizey, Synthetic Reactions 2:65 (1974)) of chemical formula VI according to the bromo-acid of chemical formula V.The bromacyl chloride of chemical formula VI and NH (Z 1) (Z 2) (Z wherein 1And Z 2Be independently of one another-(C 1-C 4Alkyl) group) chooses wantonly at alkali Na for example 2CO 3There is reaction down, so that the reaction intermediate according to chemical formula VII to be provided, shown in following scheme 4:
Scheme 4
Wherein, W is-C (Ar 1) (Ar 2), Ar wherein 1For-C 3-C 8Cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; Ar 2Be phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; R 2For halogen ,-C 1-C 3Alkyl ,-O-(C 1-C 3Alkyl) ,-NH (C 1-C 3Alkyl) or-N (C 1-C 3Alkyl) 2M is the integer of 0-4; And Z 1And Z 2Independently be-(C separately 1-C 4Alkyl).
4.2.5. preparation method according to the compound of Formula I
In another embodiment, the present invention relates to prepare according to the compound of Formula I method such as but not limited to compound (7), comprise that the compound (for example compound (5)) that makes according to Formula I V and compound (for example compound (6)) according to chemical formula VII react in the presence of suitable non-nucleophilic base, shown in following scheme 5:
Scheme 5
Figure A20058000352201151
Ar 1For-C 3-C 8Cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; Ar 2Be phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; Z 1And Z 2Independently be-(C separately 1-C 4Alkyl) group; R 2For halogen ,-C 1-C 3Alkyl ,-O-(C 1-C 3Alkyl) ,-NH (C 1-C 3Alkyl) or-N (C 1-C 3Alkyl) 2R 3And R 4Independent separately be H or-(C 1-C 4Alkyl); N is the integer of 1-4; M is the integer of 0-4.In certain embodiments, be connected to according to Formula I V compound or by the phenyl moiety that it forms and be substituted with one or more R according to the piperidine ring 4-position of chemical formula i compound 2Group, wherein R 2Definition as above.
The reaction of scheme 5 is preferably carried out in containing the solvent of polar proton inert solvent.The example that can be used for the suitable polar proton inert solvent in the reaction of scheme 5 includes but not limited to N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO).In certain embodiments, polar proton inert solvent is dimethyl formamide or N,N-DIMETHYLACETAMIDE.In specific embodiments, polar proton inert solvent is a dimethyl formamide.
In the reaction of scheme 5, the starting point concentration of the compound of the Formula I V of existence is the about 1.0M of about 0.05M-, the about 0.5M of about 0.1M-or the about 0.3M of about 0.2M-.
In certain embodiments, the reaction of scheme 5 is also carried out in the presence of suitable non-nucleophilic base, and described non-nucleophilic base is such as but not limited to triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate or 2,3,4,6,7,8,9,10-octahydro-Mi Dingbing [1,2-α] azepine (DBU).In certain embodiments, non-nucleophilic base is triethylamine, yellow soda ash or salt of wormwood.In specific embodiments, non-nucleophilic base is a yellow soda ash.
In certain embodiments, be used for the non-nucleophilic base level of reaction of scheme 5 for respect to about 1 molar equivalent-Yue 4 molar equivalents or about 1.5 molar equivalents-Yue 3 molar equivalents or about 2 molar equivalents-Yue 2.5 molar equivalents of Formula I V compound starting point concentration.
In certain embodiments, be used for scheme 5 reaction be about 0.6 molar equivalent-Yue 3 molar equivalents or about 0.8 molar equivalent-Yue 2 molar equivalents or about 1 molar equivalent-Yue 1.5 molar equivalents according to the initial level of chemical formula VII compound with respect to Formula I V compound starting point concentration.In specific embodiments, be used for scheme 5 reaction be about 1 molar equivalent according to the initial level of chemical formula VII compound with respect to Formula I V compound starting point concentration.
The reaction of scheme 5 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.The reaction of scheme 5 can be carried out in inert atmosphere.In a specific non-limiting embodiments, being reflected under the nitrogen atmosphere of scheme 5 carried out.In another specific non-limiting side's embodiment, being reflected under the argon atmospher of scheme 5 carried out.
In certain embodiments, according to about 25 ℃-Yue 175 ℃ of being reflected at of scheme 5, at about 50 ℃-Yue 150 ℃ or under about 75 ℃-Yue 125 ℃ temperature, carry out.In specific embodiments, according to carrying out under the about 100 ℃ temperature of being reflected at of scheme 5.
The sufficiently long time is carried out in the reaction of scheme 5 so that the compound of Formula I V is converted into the compound of Formula I.In one embodiment, the reaction of scheme 5 proceeds to that initiator (that is: the compound of Formula I V) exhausts or in another embodiment, and the ratio that reaction proceeds to product (according to the compound of Formula I) and initiator (being the compound of Formula I V) remains unchanged substantially.Usually, the time that is enough to the scheme of finishing 5 reaction is about 8 hours-Yue 48 hours, about 12 hours-Yue 36 hours or about 16 hours-Yue 24 hours.
The process of scheme 5 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.
Compound according to scheme 5 synthetic Formula I can utilize methods known in the art, reagent and equipment to emanate and/or purifying, includes but not limited to that following 5.5 joints are disclosed.
4.2.6. prepare the method for compound (7) according to scheme 1-5
Therefore, the method for the top scheme 1-5 of combination and reagent are to provide the method for synthesizing according to the compound of Formula I.For example, shown in scheme 6, synthesize according to disclosed method and condition in above-mentioned 4.2.1-4.2.5 joint as compound (7) according to chemical formula i compound.
Scheme 6
Figure A20058000352201181
4.2.7. the preparation method of compound (9)
In another embodiment, the present invention relates to prepare the method for compound (9) (4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines), comprise compound (8) (4-cyano group-4-phenyl-piperidinium chloride ) and sodiumazide are reacted in the presence of suitable zinc salt, shown in the following scheme 7:
Scheme 7
Figure A20058000352201191
In certain embodiments, be connected to according to compound (8) (commercially available) with by the phenyl moiety of the piperidine ring 4-position of its other compound that forms and be substituted with one or more R 2Group, wherein R 2Definition as above.
Being reflected in the solvent that contains polar proton inert solvent of scheme 7 carried out.The example of suitable polar proton inert solvent that is used for the reaction of scheme 7 includes but not limited to two  alkane, N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE or dimethyl sulfoxide (DMSO).
In certain embodiments, described solvent comprises the mixture of water and suitable polar proton inert solvent.In this embodiment, the ratio of water and polar proton inert solvent can be about 10: about 1: 1 (water: polar proton inert solvent) of 1-; About 5: about 1: 1 (water: polar proton inert solvent) of 1-; Or about 2: about 1: 1 (water: polar proton inert solvent) of 1-.In certain embodiments, polar proton inert solvent is two  alkane.In specific embodiments, solvent is 64: 36 a water: two  alkylating mixtures.
In certain embodiments, be used for the initial level of zinc salt of reaction of scheme 7 for respect to about 1 molar equivalent-Yue 5 molar equivalents or about 2 molar equivalents-Yue 4 molar equivalents of compound (8).In other embodiments, the reaction of scheme 7 use is carried out with respect to the zinc salt of about 3 molar equivalents of compound (8).In other embodiments, the reaction of scheme 7 use is carried out with respect to the zinc salt of about 2 molar equivalents of compound (8).In specific embodiments, the reaction of scheme 7 use is carried out with respect to the zinc salt of about 1 molar equivalent of compound (8).Zinc salt is the zinc salt of any appropriate, comprises ZnBr but can be selected from 2, ZnCl 2And ZnI 2Zinc halide and other suitable zinc salt such as Zn (ClO arbitrarily 4) 2Or Zn (CF 3SO 3) 2In certain embodiments, zinc salt is to be selected from ZnBr 2, ZnCl 2And ZnI 2Zinc halide.In specific embodiments, zinc salt is ZnBr 2
In certain embodiments, be used for the initial level of sodiumazide of reaction of scheme 7 for respect to about 1 molar equivalent-Yue 5 molar equivalents or about 2 molar equivalents-Yue 4 molar equivalents of compound (8).In specific embodiments, the reaction of scheme 7 use is carried out with respect to the sodiumazide of about 2 molar equivalents of compound (8).
The reaction of scheme 7 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.The reaction of scheme 7 can be carried out in inert atmosphere.In a specific non-limiting embodiments, being reflected under the nitrogen atmosphere of scheme 7 carried out.In another specific non-limiting embodiments, being reflected under the argon atmospher of scheme 7 carried out.
In certain embodiments, according to about 70 ℃-Yue 120 ℃ of being reflected at of scheme 7, at about 80 ℃-Yue 110 ℃ or under about 90 ℃-Yue 100 ℃ temperature, carry out.
The process of scheme 7 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.In one embodiment, the reaction of scheme 7 proceeds to initiator compound (8) and exhausts, or in another embodiment, the ratio that proceeds to product compound (9) and initiator compound (8) remains unchanged substantially.
In certain embodiments, the reaction of scheme 7 uses the solution of compound (8) to carry out, and wherein the starting point concentration of compound (8) is the about 3.0M of about 0.01M-, the about 2.0M of about 0.025M-, the about 1.0M of about 0.05M-or is about 0.5M of about 0.1M-or the about 0.4M of about 0.2M-.In specific embodiments, the reaction of scheme 7 uses the solution of compound (8) to carry out, and wherein the starting point concentration of compound (8) is about 0.4M.
The compound that forms in the reaction of scheme 7 (9) can utilize methods known in the art, reagent and equipment to emanate and/or purifying.In certain embodiments, the compound that forms in the reaction of scheme 7 (9) is emanated by filtration, crystallization, chromatogram or extraction.In specific embodiments, the compound that forms in the reaction of scheme 7 (9) passes through isolated by filtration.
4.2.8. preparation method according to the compound of chemical formula VIII
In another embodiment, the present invention relates to prepare the method for compound (for example compound (10)) according to chemical formula VIII, comprise compound (9) (4-phenyl-4-(2H-tetrazolium-5-yl) piperidines) and the compound (for example compound (6)) of chemical formula VII are reacted, shown in the following scheme 8:
Scheme 8
Figure A20058000352201211
Wherein, Ar 1For-C 3-C 8Cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; Ar 2Be phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; Z 1And Z 2Independently be-(C separately 1-C 4Alkyl) group; R 2For halogen ,-C 1-C 3Alkyl ,-O-(C 1-C 3Alkyl) ,-NH (C 1-C 3Alkyl) or-N (C 1-C 3Alkyl) 2M is the integer of 0-4.In certain embodiments, be connected to compound (9) and be substituted with one or more R by the phenyl moiety that it forms according to the piperidine ring 4-position of chemical formula VIII compound 2Group, wherein R 2Definition as above.
The reaction of scheme 8 is preferably carried out in containing the solvent of polar proton inert solvent.The example of suitable polar proton inert solvent that is used for the reaction of scheme 8 includes but not limited to N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO).In certain embodiments, polar proton inert solvent is dimethyl formamide or dimethyl sulfoxide (DMSO).In specific embodiments, polar proton inert solvent is a dimethyl sulfoxide (DMSO).
In the reaction of scheme 8, the starting point concentration of the compound of existence (9) is the about 3.0M of about 0.01M-, the about 2.0M of about 0.02M-, the about 1.0M of about 0.05M-, the about 0.8M of about 0.1M-or the about 0.4M of about 0.2M-.
In certain embodiments, the reaction of scheme 8 also at suitable non-nucleophilic base such as but not limited to 2,3,4,6,7,8,9,10-octahydro-Mi Dingbing [1,2-α] azepine (DBU), triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate carry out under existing.In certain embodiments, non-nucleophilic base is DBU.
In certain embodiments, be used for the non-nucleophilic base level of reaction of scheme 8 for respect to about 1 molar equivalent-Yue 10 molar equivalents or about 2 molar equivalents-Yue 8 molar equivalents or about 3 molar equivalents-Yue 5 molar equivalents of compound (9) starting point concentration.
In certain embodiments, be used for scheme 8 reaction be about 0.6 molar equivalent-Yue 3 molar equivalents or about 0.8 molar equivalent-Yue 2 molar equivalents or about 1 molar equivalent-1.5 molar equivalent according to the initial level of chemical formula VII compound with respect to compound (9) starting point concentration.
The reaction of scheme 8 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.The reaction of scheme 8 can be carried out in inert atmosphere.In a specific non-limiting embodiments, being reflected under the nitrogen atmosphere of scheme 8 carried out.In another specific non-limiting embodiments, being reflected under the argon atmospher of scheme 8 carried out.
In certain embodiments, according to about 5 ℃-Yue 50 ℃ of being reflected at of scheme 8, at about 10 ℃-Yue 40 ℃ or at about 15 ℃-Yue 30 ℃ or under about 20 ℃-Yue 25 ℃ temperature, carry out.
The sufficiently long time is carried out in the reaction of scheme 8 so that compound (9) is converted into the compound of chemical formula VIII.In one embodiment, the reaction of scheme 8 proceeds to that initiator (being compound (9)) exhausts or in another embodiment, and the ratio that reaction proceeds to product (according to the compound of Formula I X) and initiator (being compound (9)) remains unchanged substantially.Usually, the time that is enough to the scheme of finishing 8 reaction is about 5 minutes-Yue 5 hours, about 15 minutes-Yue 4 hours or about 0.5 hour-Yue 2 hours.
The process of scheme 8 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.
Compound according to scheme 8 synthetic chemical formula VIII can utilize methods known in the art, reagent and equipment to emanate and/or purifying.In certain embodiments, can emanate and/or purifying by crystallization, extraction or chromatogram according to scheme 8 synthetic chemical formula VIII compounds.
4.2.9. preparation method according to the compound of Formula I
In another embodiment, the present invention relates to preparation method according to the compound of Formula I, being included in non-nucleophilic base exists down, make according to chemical formula VIII compound (for example compound (10)) with according to the reaction of the compound (for example compound (3) or compound (11)) of Formulae II, shown in the following scheme 9:
Scheme 9
Wherein, Ar 1For-C 3-C 8Cycloalkyl, phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; Ar 2Be phenyl, naphthyl, anthryl, phenanthryl or-(5-7 unit) heteroaryl, respectively do for oneself unsubstituted or with one or more R 2Group replaces; X 1Be-Br ,-Cl or-I; Z 1And Z 2Independently be-(C separately 1-C 4Alkyl) group; R 3And R 4Independent separately be H or-(C 1-C 4Alkyl); R 2For halogen ,-C 1-C 3Alkyl ,-O-(C 1-C 3Alkyl) ,-NH (C 1-C 3Alkyl) or-N (C 1-C 3Alkyl) 2; N is the integer of 1-4; M is the integer of 0-4.In addition, in certain embodiments, the phenyl moiety that is connected to according to the piperidine ring 4-position of the compound of chemical formula VIII and Formula I is substituted with one or more R 2Group, wherein R 2Definition as above.
The reaction of scheme 9 is preferably carried out in containing the solvent of polar proton inert solvent.The example of polar proton inert solvent that is used for the reaction of scheme 9 includes but not limited to N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO).In certain embodiments, solvent is dimethyl formamide or dimethyl sulfoxide (DMSO).In specific embodiments, solvent is a dimethyl formamide.
In certain embodiments, the starting point concentration of the compound of the chemical formula VIII that exists in the reaction of scheme 9 is the about 3.0M of about 0.01M-, the about 2.0M of about 0.015M-, the about 1.0M of about 0.2M-, the about 0.8M of about 0.025M-, the about 0.6M of about 0.05M-or the about 0.2M of about 0.1M-.
The reaction of scheme 9 can be at the non-nucleophilic base of any appropriate such as but not limited to triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or (2,3,4,6,7,8,9,10-octahydro-Mi Dingbing [1,2-α] azepine) carries out under the existence (DBU).In certain embodiments, non-nucleophilic base is triethylamine, yellow soda ash or salt of wormwood.In specific embodiments, non-nucleophilic base is a salt of wormwood.
In certain embodiments, be used for the non-nucleophilic base initial level of reaction of scheme 9 for respect to about 0.5 molar equivalent-Yue 5 molar equivalents, about 1 molar equivalent-Yue 4 molar equivalents or about 2 molar equivalents-Yue 3 molar equivalents according to the starting point concentration of chemical formula VIII compound.
In certain embodiments, utilize alkylating reagent to carry out the reaction of scheme 9, the level that wherein said alkylating reagent exists is about 0.80 molar equivalent-Yue 1.5 molar equivalents, about 0.85 molar equivalent-Yue 1.2 molar equivalents, about 0.95 molar equivalent-1.1 molar equivalent with respect to the chemical formula VIII compound original bulk that exists in scheme 9 reactions.In specific embodiments, the level that exists of carrying out the employed alkylating reagent of reaction of scheme 9 is about 1.0 molar equivalents with respect to the chemical formula VIII compound original bulk that exists in the reaction.Can use the alkylating reagent of any appropriate that required product according to Formula I will be provided in the reaction of scheme 9, described alkylating reagent includes but not limited to those alkylating reagents according to Formulae II.In certain embodiments, be the haloalkyl acid amides according to the alkylating reagent of Formulae II, such as but not limited to bromoacetamide, chlor(o)acetamide or iodo-acid amide or other suitable alkylating reagent, such as but not limited to acrylamide.In certain embodiments, the alkylating reagent according to Formulae II is bromoacetamide or chlor(o)acetamide.
In specific embodiments, the alkylating reagent according to Formulae II is a chlor(o)acetamide.In another particular, can be that chlor(o)acetamide and alkylated reaction carry out in the presence of the iodide of catalytic amount according to the alkylating reagent of Formulae II.These iodide on the one hand that are used for scheme 9 reactions can metal-salt (MI p) form add, wherein M is I family or III family metal.When M is I family metal, p=1, when M is II family metal, p=2.In certain embodiments, iodide are provided as LiI, NaI, KI, CsI, CaI 2, MgI 2Or SrI 2Salt.In certain embodiments, the iodide salt that is used for scheme 9 reaction comprises potassiumiodide, sodium iodide, lithium iodide and cesium iodide and tetra-allkylammonium iodide.In certain embodiments, iodide salt is NaI or KI.When using, with respect in according to scheme 9 reaction, exist according to chemical formula VIII compound original bulk, the original bulk that is present in the iodide salt in scheme 9 reactions is about 0.01 molar equivalent-Yue 1.0 molar equivalents, about 0.05 molar equivalent-0.8 molar equivalent, about 0.1 molar equivalent-Yue 0.6 molar equivalent or about 0.2 molar equivalent-Yue 0.4 molar equivalent.
In each embodiment, scheme 9 be reflected at about 30 ℃-Yue 90 ℃ of temperature; About 40 ℃-Yue 80 ℃ of temperature; Or under about 50 ℃-Yue 70 ℃ of temperature, carry out.In specific embodiments, scheme 9 is reflected under about 60 ℃ of temperature and carries out.
The sufficiently long time is carried out in the reaction of scheme 9 so that the compound of chemical formula VIII is converted into the compound of Formula I.In one embodiment, proceed to that initiator (for example compound of chemical formula VIII) exhausts or in another embodiment according to the reaction of scheme 9, the ratio that reaction proceeds to product (according to the compound of Formula I) and initiator (according to the compound of chemical formula VIII) remains unchanged substantially.Usually, the time that is enough to the scheme of finishing 9 reaction is about 1 hour-Yue 16 hours, about 2 hours-Yue 8 hours, about 3 hours-Yue 6 hours or about 4 hours-Yue 5 hours.
In certain embodiments, being reflected in the inert atmosphere of scheme 9 carried out.Of this embodiment non-limiting aspect, being reflected under the nitrogen atmosphere of scheme 9 carried out.Another of this embodiment non-limiting aspect, being reflected under the argon atmospher of scheme 9 carried out.
The process of scheme 9 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC "), nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.
Compound according to scheme 9 synthetic Formula I can utilize methods known in the art, reagent and equipment to emanate and/or purifying.In certain embodiments, utilize crystallization, chromatogram (for example, on the silica gel) according to the compound of scheme 9 synthetic Formula I or after will adding in the entry according to the reaction mixture of scheme 9 extraction with an organic solvent emanate.In specific embodiments, emanate by crystallization according to the compound of scheme 9 synthetic Formula I.
4.2.10. prepare the method for compound (7) according to scheme 7-9
In another embodiment, the present invention relates to the synthetic of 4-tetrazyl-4-Phenylpiperidine compound, wherein make up the method for such scheme 7-9 and reagent to be provided for the method for synthetic compound according to Formula I.For example, shown in the following scheme 10, save disclosed method according to above 4.2.7-4.2.9 and condition is synthesized as compound (7) according to the example of chemical formula i compound.
Scheme 10
Figure A20058000352201261
In certain embodiments, in comprising the solvent of polar proton inert solvent, carry out the conversion of compound (8) to compound (9).In certain embodiments, described polar proton inert solvent is selected from two  alkane, N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) and combination thereof.In other embodiments, described solvent comprises the suitable polar proton inert solvent and the mixture of water.In these embodiments, the ratio of water and polar proton inert solvent can be about 10: about 1: 1 (water: in scope polar proton inert solvent) of 1-.
In certain embodiments, the polar proton inert solvent in the mixture is two  alkane.
4.2.11. the preparation method of compound (14) (4-phenyl-4-(1H-tetrazolium-5-yl) piperidines-1-carboxylic acid tert-butyl ester)
In another embodiment, the present invention relates to the preparation method of compound (14) (4-phenyl-4-(1H-tetrazolium-5-yl) piperidines-1-carboxylic acid tert-butyl ester), be included in the water-containing solvent, compound (9) (4-phenyl-4-(2H-tetrazolium-5-yl) piperidines) and compound (12) (heavy carbonic di tert butyl carbonate) are reacted, shown in the following scheme 11 in the presence of suitable alkali.
Scheme 11
In certain embodiments, the initial level of the heavy carbonic di tert butyl carbonate that uses in the reaction of scheme 11 is about 1 molar equivalent-Yue 3 molar equivalents or about 1 molar equivalent-Yue 2.5 molar equivalents with respect to compound (9).In other embodiments, scheme 11 reaction uses are carried out with respect to the heavy carbonic di tert butyl carbonate of about 1.5 molar equivalents of compound (9).In other embodiments, the reaction of scheme 11 use is carried out with respect to the heavy carbonic di tert butyl carbonate of about 1.25 molar equivalents of compound (9).In specific embodiments, scheme 11 reaction uses are carried out with respect to the heavy carbonic di tert butyl carbonate of about 1.1 molar equivalents of compound (9).
In certain embodiments, be used for the initial level that the alkali of scheme 11 reaction exists and be about 1 molar equivalent-Yue 3 molar equivalents or about 1 molar equivalent-Yue 2.5 molar equivalents with respect to compound (9).In specific embodiments, the reaction of scheme 11 use is carried out with respect to the alkali of about 2.2 molar equivalents of compound (9).Described alkali is the alkali of any appropriate, but can be selected from NaOH and KOH.In specific embodiments, described alkali is NaOH.
The reaction of scheme 11 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.The reaction of scheme 11 can be carried out in inert atmosphere.In a specific non-limiting embodiments, being reflected under the nitrogen atmosphere of scheme 11 carried out.In another specific non-limiting embodiments, being reflected under the argon atmospher of scheme 11 carried out.
In certain embodiments, scheme 11 be reflected at about 5 ℃-Yue 100 ℃, at about 10 ℃-Yue 75 ℃ or under about 15 ℃-Yue 50 ℃ temperature, carry out.In specific non-limiting embodiments, being reflected under the room temperature (promptly about 20 ℃-Yue 25 ℃) of scheme 11 carried out.
The process of scheme 11 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.In one embodiment, the reaction of scheme 11 proceeds to initiator compound (9) and exhausts, or in another embodiment, the ratio that reaction proceeds to product compound (14) and initiator compound (9) remains unchanged substantially.
In certain embodiments, the reaction of scheme 11 uses the solution of compound (9) to carry out, and wherein the starting point concentration of compound (9) is the about 2M of about 0.1M-, the about 1.5M of about 0.25M-or the about 1.25M of about 0.5M-.In specific embodiments, the reaction of scheme 11 uses the solution of compound (9) to carry out, and wherein the starting point concentration of compound (9) is about 0.8M.
The compound that forms in the reaction of scheme 11 (14) can utilize methods known in the art, reagent and equipment to emanate and/or purifying.In certain embodiments, the compound that forms in the reaction of scheme 11 (14) is emanated by filtration, crystallization, chromatogram or extraction.In specific embodiments, the compound that forms in the reaction of scheme 11 (14) is emanated by filtering.
4.2.12. the method for synthetic compound 13 (4-cyano group-4-Phenylpiperidine-1-carboxylic acid tert-butyl ester)
In another embodiment, the present invention relates to be used for the method for synthetic compound (13) (4-cyano group-4-Phenylpiperidine-1-carboxylic acid tert-butyl ester), comprise and make compound (16) (4-cyano group-4-phenyl-piperidines: the free alkali of compound (8) (4-cyano group-4-phenyl-piperidinium chloride )) with compound (2) (heavy carbonic di tert butyl carbonate) reaction, shown in the following scheme 12.
Scheme 12
In certain embodiments, the initial level of the heavy carbonic di tert butyl carbonate existence of using in scheme 12 reactions is about 1 molar equivalent-Yue 3 molar equivalents or about 1 molar equivalent-Yue 2.5 molar equivalents with respect to compound (16).In other embodiments, scheme 12 reaction uses are carried out with respect to the heavy carbonic di-t-butyl of about 1.5 molar equivalents of compound (16).In other embodiments, the reaction of scheme 12 use is carried out with respect to the heavy carbonic di tert butyl carbonate of about 1.25 molar equivalents of compound (16).In specific embodiments, the reaction of scheme 12 use is carried out with respect to the heavy carbonic di tert butyl carbonate of about 1.1 molar equivalents of compound (16).
In certain embodiments, be used for the initial level that the alkali of scheme 12 reaction exists and be about 1 molar equivalent-Yue 3 molar equivalents or about 1 molar equivalent-Yue 2.5 molar equivalents with respect to compound (16).Described alkali is the alkali of any appropriate, but can be selected from NaOH and KOH.Of this embodiment non-limiting aspect, described alkali is NaOH.
The reaction of scheme 12 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.In certain embodiments, the reaction of scheme 12 can be carried out in inert atmosphere.Of this embodiment non-limiting aspect, being reflected under the argon atmospher of scheme 12 carried out.In another non-limiting embodiments, being reflected under the nitrogen atmosphere of scheme 12 carried out.
In certain embodiments, scheme 12 be reflected at about 5 ℃-Yue 100 ℃, about 10 ℃-Yue 75 ℃, about 15 ℃-Yue 50 ℃ temperature or under room temperature (promptly about 20 ℃-Yue 25 ℃), carry out.
The process of scheme 12 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.In one embodiment, the reaction of scheme 12 proceeds to initiator compound (16) and exhausts, or in another embodiment, the ratio that reaction proceeds to product compound (13) and initiator compound (16) remains unchanged substantially.
In certain embodiments, the reaction of scheme 12 uses the solution of compound (16) to carry out, and wherein the starting point concentration of compound (16) is the about 2M of about 0.1M-, the about 1.5M of about 0.25M-or the about 1.25M of about 0.5M-.Of this embodiment non-limiting aspect, the reaction of scheme 12 can use compound (16) starting point concentration of about 0.8M to carry out.
The compound that forms in the reaction of scheme 12 (13) can utilize methods known in the art, reagent and equipment to emanate and/or purifying.In certain embodiments, the compound that forms in the reaction of scheme 12 (13) is emanated by filtration, crystallization, chromatogram or extraction.
4.2.13. the alternative method of synthetic compound (14) (4-phenyl-4-(1H-tetrazolium-5-yl) piperidines-1-carboxylic acid tert-butyl ester)
In one embodiment, the present invention relates to prepare the method for compound (14) (4-phenyl-4-(1H-tetrazolium-5-yl) piperidines-1-carboxylic acid tert-butyl ester), comprise compound (13) (4-cyano group-4-Phenylpiperidine-1-carboxylic acid tert-butyl ester) and sodiumazide are reacted that described zinc salt is such as but not limited to zinc halide (ZnBr for example in the presence of zinc salt 2, ZnCl 2And ZnI 2) or other suitable zinc salt such as Zn (ClO 4) 2Or Zn (CF 3SO 3) 2, shown in the following scheme 13:
Scheme 13
Figure A20058000352201301
In some optional embodiment, the phenyl moiety that is connected to the piperidine ring 4-position of compound (13) is substituted with one or more R 2Group, wherein R 2Definition as above.
The reaction of scheme 13 is preferably carried out in containing the solvent of polar proton inert solvent.The example that can be used for the suitable polar proton inert solvent in the reaction of scheme 13 includes but not limited to N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO).In certain embodiments, solvent is N-Methyl pyrrolidone or N,N-DIMETHYLACETAMIDE.Of this embodiment non-limiting aspect, solvent is a N-Methyl pyrrolidone.
In certain embodiments, the solvent that is used for the reaction of scheme 13 is the suitable polar proton inert solvent and the mixture of water.In this embodiment, the ratio of polar proton inert solvent and water can be about 50: about 2: 1 (v/v) (polar proton inert solvents: water) of 1-; About 20: about 4: 1 (polar proton inert solvents: water) of 1-; Or about 15: about 10: 1 (polar proton inert solvents: water) of 1-.
In certain embodiments, the reaction of scheme 13 uses initial level for to carry out with respect to about 1 molar equivalent-Yue 5 molar equivalents of compound (13) or the zinc salt of about 2 molar equivalents-Yue 4 molar equivalents.In other embodiments, the reaction of scheme 13 use is carried out with respect to the zinc salt of about 3 molar equivalents of compound (13).Zinc salt can be selected from and comprise ZnBr 2, ZnCl 2And ZnI 2Zinc halide and other suitable zinc salt such as Zn (ClO arbitrarily 4) 2Or Zn (CF 3SO 3) 2Of this embodiment non-limiting aspect, zinc salt can be ZnBr 2Zinc salt can be available from for example Aldrich Chemical Co., Milwaukee, Wisconsin.
In certain embodiments, the reaction of scheme 13 uses original bulk for to carry out with respect to about 1 molar equivalent-Yue 5 molar equivalents of compound (13) or the sodiumazide of about 2 molar equivalents-Yue 4 molar equivalents.Of this embodiment non-limiting aspect, the reaction of scheme 13 uses the sodiumazide with respect to about 4 molar equivalents of compound (13) to carry out.
In certain embodiments, compound (13) provides as salt, hydrochloride for example, it can utilize program known in the art, with reaction of sodium azide before be converted into unhindered amina.For example, the hydrochloride of compound (13) is dissolved in suitable organic solvent such as but not limited in the chloroform, and so that solution to be provided, this soln using is Na for example 2CO 3Saturated aqueous solution extraction.Reclaim organic layer and utilize the organic solvent reextraction water layer of additional volumes.Merge organic solvent, the water extraction, drying is evaporated so that the compound as unhindered amina (13) to be provided subsequently for example through anhydrous sodium sulfate drying.
The reaction of scheme 13 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.In certain embodiments, the reaction of scheme 13 can be carried out in inert atmosphere.Of this embodiment non-limiting aspect, being reflected under the nitrogen atmosphere of scheme 13 carried out.Another of this embodiment non-limiting aspect, being reflected under the argon atmospher of scheme 13 carried out.
In certain embodiments, scheme 13 is reflected at about 100 ℃-Yue 200 ℃; At about 120 ℃-Yue 150 ℃ or under about 130 ℃-Yue 140 ℃ temperature, carry out.
The process of the reaction of scheme 13 can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.In one embodiment, the reaction of scheme 13 proceeds to initiator and exhausts, or in another embodiment, the ratio that proceeds to product compound (14) and initiator compound (13) remains unchanged substantially.
In certain embodiments, the reaction of scheme 13 uses the solution of compound (13) to carry out, and wherein the starting point concentration of compound (13) is about 1.0M of about 0.05M-or the about 0.5M of about 0.1M-.Of this embodiment non-limiting aspect, the starting point concentration of compound in the reaction of scheme 4 (13) can be about 0.25M.
The compound that forms in the reaction of scheme 13 (14) can utilize methods known in the art, reagent and equipment to emanate and/or purifying.
4.2.14. the compound of chemical formula X is synthetic
In another embodiment, the present invention relates to prepare the method for compound (for example compound (15)) according to chemical formula X, comprise making compound (14) (4-phenyl-4-(1H-tetrazolium-5-yl) piperidines-1-carboxylic acid tert-butyl ester) and in the presence of non-nucleophilic base, reacting according to the alkylating reagent of Formulae II, shown in the following scheme 14:
Scheme 14
Wherein, n is the integer of 1-4, R 3And R 4Independent separately be H or-(C 1-C 4Alkyl) and X 1Be-Br ,-Cl or-I.In certain embodiments, be connected to compound (14) and randomly be substituted with one or more R by the phenyl moiety that it forms according to the piperidine ring 4-position of the compound of chemical formula X 2Group, wherein R 2Definition as above.
The reaction of scheme 14 is preferably carried out in containing the solvent of polar proton inert solvent.The example that can be used for the suitable polar proton inert solvent in the reaction of scheme 14 includes but not limited to acetone, N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO).In specific embodiments, solvent is an acetone.
The starting point concentration of the compound (14) that exists in the reaction of scheme 14 in certain embodiments, is about 0.8M of about 0.1M-or the about 0.6M of about 0.2M-.The starting point concentration of the compound (14) that exists in the reaction of scheme 5 in specific embodiments, is about 0.4M.
The reaction of scheme 14 can be at the non-nucleophilic base of any appropriate such as but not limited to triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate or 2,3,4,6,7,8,9, and 10-octahydro-Mi Dingbing [1,2-α] azepine (DBU) carries out under existing.In certain embodiments, non-nucleophilic base is triethylamine, yellow soda ash or salt of wormwood.In certain embodiments, be present in non-nucleophilic base level in the reaction of scheme 14 for respect to about 0.5 molar equivalent-Yue 3.0 molar equivalents of compound (14) starting point concentration, about 0.75 molar equivalent-Yue 2.0 molar equivalents or about 1.0 molar equivalents-Yue 1.5 molar equivalents.In specific embodiments, non-nucleophilic base is a salt of wormwood.In specific embodiments, the reaction of scheme 14 use is carried out with respect to the non-nucleophilic base of about 1 molar equivalent of compound (14) starting point concentration.
In certain embodiments, the reaction utilization of scheme 14 is carried out with respect to the alkylating reagent level of about 0.80 molar equivalent-Yue 1.5 molar equivalents of the compound that exists in the reaction according to scheme 14 (14) original bulk, about 0.85 molar equivalent-Yue 1.2 molar equivalents or about 0.95 molar equivalent-1.1 molar equivalent.In specific embodiments, the reaction utilization of scheme 14 is carried out with respect to the alkylating reagent according to about 1 molar equivalent of compound (14) original bulk of existence in scheme 14 reactions.Comprise that the alkylating reagent according to any appropriate of the compound of Formulae II all can be used for the reaction of scheme 14, this reaction will provide the expectation product according to chemical formula X.In certain embodiments, be the haloalkyl acid amides according to the alkylating reagent of Formulae II, such as but not limited to bromoacetamide, chlor(o)acetamide or iodo-acid amide.In other non-limiting embodiments, alkylating reagent is an acrylamide.In certain embodiments, the alkylating reagent according to Formulae II is bromoacetamide or chlor(o)acetamide.In specific embodiments, be bromoacetamide (compound (3)) according to the alkylating reagent of Formulae II, and in another particular, be chlor(o)acetamide (compound (11)) according to the alkylating reagent of Formulae II.
In certain embodiments, alkylated reaction carries out in the presence of the iodide of catalytic amount.These iodide on the one hand that are used for scheme 14 reactions can metal-salt (MI p) form add, wherein M is I family or II family metal.P=1, then M is an I family metal, p=2, then M is an II family metal.In certain embodiments, iodide are provided as LiI, NaI, KI, CsI, CaI 2, MgI 2Or SrI 2Salt.In certain embodiments, the iodide salt that can be used in scheme 14 reactions comprises potassiumiodide, sodium iodide, lithium iodide and cesium iodide and tetra-allkylammonium iodide.In certain embodiments, iodide are NaI or KI.When using, the initial level that is present in the iodide salt in scheme 14 reactions is about 0.01 molar equivalent-Yue 2.0 molar equivalents, about 0.05 molar equivalent-Yue 1.0 molar equivalents, about 0.1 molar equivalent-Yue 0.6 molar equivalent or about 0.1 molar equivalent-Yue 0.25 molar equivalent with respect to the original bulk of compound (14).
In certain embodiments, scheme 14 is reflected at about 20 ℃-Yue 100 ℃ of temperature; About 25 ℃-Yue 80 ℃ of temperature; Or under about 30 ℃-Yue 70 ℃ temperature, carry out.In specific embodiments, being reflected under the about 40 ℃-Yue 50 ℃ temperature of scheme 14 carried out.
The sufficiently long time is carried out in the reaction of scheme 14, so that compound (14) is converted into the compound of chemical formula X.In one embodiment, proceed to that initiator (for example compound (14)) exhausts or in another embodiment according to the reaction of scheme 14, the ratio that reaction proceeds to product (according to the compound of chemical formula X) and initiator (compound (14)) remains unchanged substantially.Usually, the time that is enough to the scheme of finishing 14 reaction is about 4 hours-Yue 48 hours, about 8 hours-Yue 36 hours or about 12 hours-Yue 24 hours.In specific embodiments, carried out about 16 hours according to the reaction of scheme 14.
The reaction of scheme 14 can be in decompression, normal pressure or pressurization promptly greater than carrying out under the normal pressure.In one embodiment, be reflected under the normal pressure and carry out.In certain embodiments, the reaction of scheme 14 can be carried out in inert atmosphere.Of this embodiment non-limiting aspect, being reflected under the nitrogen atmosphere of scheme 14 carried out.Another of this embodiment non-limiting aspect, being reflected under the argon atmospher of scheme 14 carried out.
The process of the reaction of scheme 14 can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC "), nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.
Compound according to scheme 14 synthetic chemical formula X can utilize methods known in the art, reagent and equipment to emanate and/or purifying.
4.2.15. the compound of Formula I V is synthetic
In another embodiment, the present invention relates to prepare the method for compound (for example compound (5)), comprise the de-protected step of piperidines nitrogen that makes according to the compound of chemical formula X according to Formula I V, shown in the following scheme 15:
Scheme 15
Figure A20058000352201351
Wherein, n is the integer of 1-4, R 3And R 4Independent separately be H or-(C 1-C 4Alkyl).In certain embodiments, be connected to according to the compound of chemical formula X and by the phenyl moiety that it forms and be substituted with one or more R according to the piperidine ring 4-position of the compound of Formula I V 2Group, wherein R 2Definition as above.
The reaction of scheme 15 is preferably carried out in solvent, and described solvent is such as but not limited to methylene dichloride (CH 2Cl 2) or 1,2-ethylene dichloride (ClCH 2CH 2Cl).In specific embodiments, described solvent is a methylene dichloride.
In the reaction of scheme 15, the starting point concentration that the compound of chemical formula X exists is the about 0.8M of about 0.025M-, the about 0.4M of about 0.05M-or the about 0.2M of about 0.1M-.
In certain embodiments, the reaction of scheme 15 is also carried out such as but not limited in the presence of the trifluoroacetic acid at suitable acid catalyst.Also can adopt other method of the Boc of removing known in the art part, for example comprise under 25 ℃, at the HCl of 3M (aqueous solution)React in/the ethyl acetate.
In certain embodiments, be used for initial level that the acid catalyst of the reaction of scheme 15 exists and be about 1 molar equivalent-Yue 4 molar equivalents with respect to the starting point concentration of the compound of chemical formula X.In specific embodiments, be used for initial level that the acid catalyst of the reaction of scheme 15 exists and be about 2 molar equivalents-Yue 3 molar equivalents with respect to the starting point concentration of the compound of chemical formula X.
In certain embodiments, the compound according to chemical formula X is dissolved in the solvent such as but not limited under the argon atmospher at inert atmosphere.In this embodiment on the other hand, contain the container that comprises according to the reaction mixture of the solution of the compound of chemical formula X and acid catalyst with argon purge.The argon gas that is reflected at according to scheme 15 is existed down, at about normal pressure (about 14.7psi (pound/square inch))-Yue 500psi, carry out at about normal pressure (about 14.7psi)-Yue 100psi or under the pressure of about normal pressure (about 14.7psi)-Yue 25psi.
In certain embodiments, according to about 5 ℃-Yue 100 ℃ of being reflected at of scheme 15, at about 10 ℃-Yue 75 ℃ or under about 15 ℃-Yue 30 ℃ temperature, carry out.
The sufficiently long time is carried out in the reaction of scheme 15 so that the compound of chemical formula X is converted into the compound of Formula I V.In one embodiment, the reaction of scheme 15 proceeds to that initiator (compound of chemical formula X) exhausts or in another embodiment, and the ratio that reaction proceeds to product (compound of Formula I V) and initiator (compound of chemical formula X) remains unchanged substantially.Usually, the time that is enough to the scheme of finishing 15 reactions is about 1 hour-Yue 48 hours, about 2 hours-Yue 36 hours, or about 4 hours-Yue 24 hours.In specific embodiments, the reaction of scheme 6 was carried out about 16 hours.
The process of scheme 15 reactions can utilize the traditional analysis technology to monitor, include but not limited to liquid chromatography and mass spectrometry (" LC/MS "), thin-layer chromatography (" TLC "), high performance liquid chromatography (" HPLC "), gas-chromatography (" GC "), gas-liquid chromatograph (" GLC ") and/or nuclear magnetic resonance spectrum (" NMR "), as 1H and 13C NMR.
Compound according to scheme 15 synthetic Formula I V can utilize methods known in the art, reagent and equipment to emanate and/or purifying.
4.2.16. prepare the method for compound (7) according to scheme 11-15
In another embodiment, the present invention relates to the method for synthetic 4-tetrazyl-4-Phenylpiperidine compound, wherein can make up the method for such scheme 11-15 and reagent so that the method for synthetic compound according to Formula I to be provided.For example, shown in the following scheme 16, save described method and synthetic compound---the compound (7) of condition according to Formula I according to above 4.2.11-4.2.15.
Scheme 16
Figure A20058000352201381
4.2.17. prepare the method for compound (18) 5-phenyl-2H-tetrazolium
In another implementation method, the present invention relates to the method for synthetic compound (18) (5-benzyl-2H-tetrazolium), comprise compound (17) (2-phenyl-acetonitrile or benzonitrile) (commercially available) and sodiumazide are reacted in the presence of Triethylammonium chloride, shown in the following scheme 17:
Scheme 17
Figure A20058000352201391
In one embodiment, at 95 ℃-100 ℃, in toluene, handled commercial compound (17) 16 hours with sodiumazide and Triethylammonium chloride down at rare gas element (for example argon gas).In other embodiments, according to the method for above scheme 1,7 and 13 and the method described in following 5.1 joint embodiment 1 and the 5.17 joint embodiment 17, nitrile (compound (17)) can be converted into corresponding tetrazolium (compound (18)).In the others of this embodiment, the phenyl moiety of compound (17) is chosen wantonly and is substituted with one or more R 2Group provides to comprise this R thus 2The compound of the corresponding Formula I of part.
4.2.18. the preparation method of compound (20) 5-benzyl-2-(2-phenyl the third-2 base)-2H-tetrazolium
In another embodiment, the present invention relates to the method for synthetic compound (20) (5-benzyl-2-(2-phenyl the third-2 base)-2H-tetrazolium), comprise making compound (18) and compound (19) (1-(third-1-alkene-2-yl) benzene) reaction, shown in the following scheme 18:
Scheme 18
In this way, compound (18) can be by reacting with compound (19) and trichoroacetic acid(TCA) under the condition that for example provides in following 5.17 joints, embodiment 17, in chloroform and being protected substantially fully on 2.
As an alternative in the embodiment of scheme, the tetrazolium part of compound (18) can be protected by following reaction at other: a) under reflux temperature in toluene with the reaction of trityl alcohol; B) under reflux temperature in acetonitrile with the 2-bromoacetamide and the K of trityl as protecting group 2CO 3Reaction; C) under reflux temperature in acetonitrile with toluene sulfonyl chloride and K 2CO 3Reaction; D) at room temperature in acetonitrile with 2,4-dinitrofluorobenzene and K 2CO 3Reaction; Or e) under reflux temperature in acetonitrile with benzene sulfonyl chloride and K 2CO 3Reaction.
4.2.19. the synthetic method of the compound of chemical formula XII
In another embodiment, the present invention relates to synthesize method according to the tetrazole compound that is obstructed (for example compound (22) and compound (24)) of chemical formula XII, comprise make compound (20) (5-benzyl-2-(2-phenyl the third-2 base)-2H-tetrazolium) with according to the reaction of the compound of chemical formula XI, as described in following 5.11 and 5.19 joints and shown in the following scheme 19:
Scheme 19
Figure A20058000352201411
Wherein, each X 1Be independently selected from Cl, Br or I, R 5Be nitrogen-protecting group, it can be selected from but be not limited to following group:
In another embodiment, R 5Be
The compound of chemical formula XI is compound (35)
Figure A20058000352201414
In specific embodiments, in diethyl ether, utilize 2 normal n-Butyl Lithiums, make compound (20) and compound (21) reaction, shown in the following scheme 20, so that boc to be provided the piperidine compounds (22) of protection:
Scheme 20
Figure A20058000352201421
In another particular, in diethyl ether, utilize 2 normal n-Butyl Lithiums, make compound (20) and the compound (23) (can be from Acros; Morris Plains; NJ buys) reaction, shown in the following scheme 21, so that the piperidine compounds (24) of tosyl group protection to be provided:
Scheme 21
Figure A20058000352201422
Preparation and using method thereof according to the compound of chemical formula XI are described in Chambers et al. (J.Med.Chem. (1992) 35: 2033-39) and in the following 4.2.25 joint.
4.2.20. the synthetic method of the compound of chemical formula XIII
In another embodiment, the present invention relates to synthesize method, comprise the protecting group (R of the compound of removing chemical formula XII according to the compound (for example compound (14) and compound (25)) of chemical formula XIII 5), shown in the following scheme 22:
Scheme 22
Figure A20058000352201431
In specific embodiments, can in ethanol, in the presence of potassium formiate and Pd/C, remove the cumyl protecting group of compound (22), have de-protected tetrazolium compound (14) partly to provide, shown in scheme 23:
Scheme 23
Figure A20058000352201432
In another particular; can in ethanol, in the presence of potassium formiate and Pd/C, remove the cumyl protecting group of compound (24); so that the compound (25) that has de-protected tetrazolium part to be provided, as described in following 5.20 joints, the embodiment 20 and shown in the scheme 24:
Scheme 24
In this embodiment on the other hand, R 5Part is a phenmethyl, and cumyl and R 5(phenmethyl) protecting group all can be removed from the compound of chemical formula XII, so that the compound as product (9) to be provided.Conversely, compound (9) can or be converted into the compound of Formula I according to scheme 10 (by the method for such scheme 8 and 9) according to scheme 16 (by the method for scheme 11,14,15 and 30).
4.2.21. the synthetic method of the compound of chemical formula XIV
In another embodiment, the present invention relates to the method for synthetic compound (for example compound (15) and compound (26)) according to chemical formula XIV, comprise that the compound that makes chemical formula XIII and the compound of Formulae II react, shown in the following scheme 25:
Scheme 25
Figure A20058000352201442
In specific embodiments, the present invention relates to the compound of synthetic chemistry formula X, comprise the step of the compound reaction that makes compound (14) and Formulae II, shown in the following scheme 26:
Scheme 26
Figure A20058000352201451
In another particular, the present invention relates to compound synthetic of chemical formula XV, comprise the step that makes compound (25) and the compound reaction of Formulae II, shown in the following scheme 27:
Scheme 27
The alkylated reaction of formula 25-27 can carry out under the disclosed condition in above 4.2.2 joint (scheme 2) and 4.2.9 joint (scheme 9) and following 5.2 joints (embodiment 2), 5.9 joints (embodiment 9), 5.12 joints (embodiment 12) and 5.21 joints (embodiment 21).
R equally, wherein 5For the compound of the chemical formula XIII of benzene methoxycarbonyl, trityl, methoxyl group trityl, phenmethyl, 9-fluorenylmethyloxycarbonyl (fluoroenylmethoxycarbonyl), t-butyldimethylsilyl, tosyl group etc. also can with compound (for example compound (3) or compound (the 11)) reaction of Formulae II, so that the compound as the chemical formula XIV of product to be provided.
4.2.22. synthesize the method for the compound of Formula I V from the compound of chemical formula XIV
In another embodiment, the present invention relates to from the method for the synthetic compound according to Formula I V of the compound of chemical formula XIV, shown in the following scheme 28:
Scheme 28
Remove the Boc base and remove the compound according to Formula I V (for example compound (5)) that tosyl group will provide correspondence from the compound of chemical formula X from the compound of chemical formula XV, shown in the following scheme 29:
Scheme 29
Figure A20058000352201471
In specific embodiments, can in methylene dichloride, utilize trifluoroacetic acid to remove the Boc protecting group of compound (15), so that compound (5) to be provided, as described in above-mentioned 4.2.15 joint (scheme 15).Similarly, can utilize mineral acid such as H 2SO 4, HCl and HBr remove the tosyl group protecting group of compound (26), so that compound (5) to be provided.In specific embodiments, utilize H 2SO 4Remove the tosyl group protecting group of compound (26).
4.2.23. synthesize the method for the compound of Formula I from the compound of Formula I V
The present invention relates to compound by making Formula I V and compound (for example compound (the 6)) reaction of chemical formula VII, from the synthetic wherein R of the compound (for example compound (5)) of Formula I V 1For-(CH 2) nC (O) N (R 3) (R 4) the method for compound (for example compound (7)) of Formula I, shown in the following scheme 30:
Scheme 30
Figure A20058000352201481
The reaction of scheme 30 can be carried out under the condition of condition that above-mentioned 4.2.5 joint (scheme 5) is provided and description in following 5.5 joints (embodiment 5).
4.2.24. prepare the method for compound (7) according to scheme 17-30
In another particular, the present invention relates to the synthetic of 4-tetrazyl-4-Phenylpiperidine compound, wherein can make up the method for such scheme 17-30 and reagent to be provided for the illustrative methods of synthetic compound according to Formula I.For example, shown in the following scheme 31, save described method and the synthetic compound-compound (7) of condition according to Formula I according to above 4.2.17-4.2.23.
According to scheme 31, (2-cyano group benzene (Aldrich, Milwaukee, WI)) is initial synthetic from commercial compound (17) for compound (7).Usually, utilize sodiumazide, Triethylammonium chloride and, make compound (17) (benzyl cyanide) be converted into compound (18) (5-benzyl-1-H-tetrazolium) as the toluene of solvent.Composite reagent also is heated to 100 ℃, continues 16 hours.Acid/alkaline purification subsequently (workup) provides the pure tetrazole compound (18) as white crystalline solid.The protection of the tetrazolium of compound (18) part can utilize that any one is finished in the kinds of protect base.In specific embodiments, the protection of the tetrazolium of compound (18) part is by finishing so that the tetrazole compound (20) of cumyl protection to be provided with the alpha-methyl styrene reaction.The formation of piperidine ring is to utilize the n-Butyl Lithium in diethyl ether to realize with generation compound (24) with two dichloro ethamine matrix (for example compound (the 23)) reactions of essential N protection.The protection of going of the tetrazolium part of compound (24) is to utilize standard hydrogenolysis condition (potassium formiate, Pd/C, EtOH, heating) to finish, so that compound (25) to be provided.Compound (25) utilizes 2-chlor(o)acetamide or the alkylation of 2-bromoacetamide, and compound (26) is provided.Make compound (26) go protection, compound (5) is provided, itself and compound (6) are reacted, so that compound (7) to be provided.
Scheme 31
4.2.25. two dichloro 1-ethanamine derivatives is synthetic
In certain embodiments, present invention resides in the synthetic middle pair dichloro 1-ethanamine derivatives that use of the compound of Formula I, wherein the compound of Formula I includes but not limited to compound (7).For example, according to the method for people such as Chambers (J.Med.Chem. (1992) 35:2033-39), prepare compound (21) usually from commercial compound (29), shown in scheme 32:
Scheme 32
Figure A20058000352201501
In the others of this embodiment, usually according to scheme 33, from compound (30) (Aldrich, Milwaukee, WI) two dichloro 1-ethanamine derivatives of preparation chemical formula XVI:
Scheme 33
Figure A20058000352201502
Wherein R6 can be selected from but be not limited to following group:
Compound (31)
Figure A20058000352201503
Compound (32)
Figure A20058000352201504
And compound (6)
To generate the compound of following chemical formula XVI:
Figure A20058000352201511
According to scheme 33, usually, with salt of wormwood and corresponding R 6-muriate or bromide add in the stirred solution of compound (30).This solution was heated to reflux temperature 8 hours, was cooled to room temperature again, subsequent filtration.Filtrate is concentrated into drying, after water treatment, is dissolved in crude product in the methyl alcohol and adds HCl (in diethyl ether).The mixture concentrate drying is dissolved in crude product methylene dichloride and dropwise adds thionyl chloride.Stirred the gained mixture 1 hour under the room temperature, remove volatile matter with final vacuum, so that the compound of chemical formula XVI to be provided.
4.2.26. prepare the other method of compound (7) according to scheme 17-33
In another embodiment, the present invention relates to the other approach of synthetic 4-tetrazyl-4-Phenylpiperidine compound, wherein can make up the method for above scheme 17-30 and reagent to be provided for the method for synthetic compound according to Formula I.For example, shown in the following scheme 34, save described method and the synthetic compound-compound (7) of condition according to Formula I according to above 4.2.17-4.2.25.
Scheme 34
Figure A20058000352201521
5. embodiment
Except as otherwise noted, the reagent and the solvent that are used for the disclosed embodiments all derive from Aldrich ChemicalCo., Milwaukee, Wisconsin (for example 1,4-two  alkane, sodiumazide, zinc bromide, DBU, DMSO, salt of wormwood) or derive from Fisher Scientific Company (Pittsburgh, Pennsylvania) (for example MTBE, isopropyl acetate, ethyl acetate, methyl alcohol and sodium sulfate).
Below alleged LC/MS analyze implement usually as follows.Utilize C18 post (Zorbax XDB-C18,4.6 * 50mm, 5 micron grain sizes; (Agilent, PaloAlto, California)) carries out liquid-phase chromatographic analysis (HPLC).Described post moves under 25 ℃ of temperature and locates monitoring at 260nm (reference 360nm).Flow rate of mobile phase is 1mL/min.The moving phase conduct is by solvent orange 2 A (0.1%TFA/H 2O) and solvent B (0.1%TFA/CH 3CN) the gradient solvent operation that mixture is formed, it has following composition: 85%A/15%B (0min), 5%A/95%B (2.3min), 5%A/95%B (4.3min), 85%A/15%B (4.4min) and 85%A/15%B (5.2min).
Quality is selected to detect (MSD) and is utilized normal pressure electric spray ion source (API-ES) to carry out as ionization mode, has straight polarity.For MSD equipment (the Agilent 1100 LC/MS (Agilent that each adopted in the following analysis, Palo Alto, California) and Waters ZQ MS (Waters, Milford, Massachusetts)) be set as follows usually: Agilent 1100 LC/MS:(a) ionization voltage program lifting (forbidding) is separated in collision, (b) ionization voltage (80) is separated in collision, (c) gain (1EMV), (d) threshold value (20), (e) step-length (0.15), (f) gas temperature (℃) (350), (g) dry gas (12.0L/min), (h) atomizer pressure (40psig), (i) Vcap (3500V), (j) peak width (0.07min), (k) MW scope (150-2000); Waters ZQ MS:(a) cone (V) (30.00), (b) extractor (V) (20.00), (c) RF lens (V) (0.3), (d) source temperature (℃) (150), (e) the cone temperature (℃) (20), (f) desolvation gas (℃) (350), (g) cone air-flow (111L/hr), (h) desolvation air-flow (615L/hr), (i) kapillary (kV), (j) LM 1 resolving power (15), (k) HM 1 resolving power (15), (l) the ion energy 1 (0.5), (m) multiplier (650).
5.1. embodiment 1: compound (2) (1-phenmethyl-4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines) synthetic
(Aldrich Chemical Co., Milwaukee add 500mLNa in 1.0L chloroformic solution Wisconsin) to stirring good 125.77g 1-phenmethyl-4-cyano group-4-Phenylpiperidine hydrochloride (hydrochloride of compound (1)) 2CO 3Saturated aqueous solution.Layering is also reclaimed chloroform layer.With about 200ml chloroform extraction water layer.The chloroform layer that merges twice recovery extracts with about 500mL deionized water, through anhydrous sodium sulfate drying and be evaporated to constant weight, obtains the compound (1) of 109.7g as unhindered amina, (1-phenmethyl-4-cyano group-4-piperidines).
Unhindered amina compound (1) (109.7g) is dissolved in the 1-Methyl-2-Pyrrolidone of 500mL and separated into two parts, uses identical flask to the parallel following steps of carrying out of two portions.
1-Methyl-2-Pyrrolidone solution (250mL contains 54.85g compound (the 1)) introducing that part is contained compound (1) is equipped with in 3.0 liters of flasks of overhead mechanical stirrer, thermometer, addition funnel and nitrogen inlet.With solvent (1-Methyl-2-Pyrrolidone of 500mL) and ZnBr 2(134.1g, 0.595mol are dissolved in the 100mL water) add in the flask.ZnBr 2Adding cause heat release, make the temperature of reaction mixture rise to about 55-60 ℃.With the solid sodiumazide (51.6g 0.794mol) all once adds, and with reaction mixture at N 2Be heated to 135 ℃ under the protection.Reaction is monitored by LC/MS, no longer can detected (7 days) until initiator (compound (1)).
Slowly compound of reaction is under agitation added in 8 liters of HCl aqueous solution (1%HCl) in the beaker.In beaker the top of liquid with argon purge to remove any hydrazoic acid that may form.About 3 hours of stirred solution is also emanated the solid that is produced by vacuum filtration.With at first dry air, the vacuum-drying subsequently of solid of collecting.Reclaim 62.49g compound (2) altogether.Parallel carry out second the reaction obtain 63.62g compound (2) ( 1H NMR (MeOHd 4): δ 7.5 (m, 5H), 7.2 (m, 5H), 3.5 (m, 2H), 3.35 (s, 2H), 3.05 (m, 4H), 2.45 (m, 2H).
5.2. embodiment 2: synthetic compound (4) (2-[5-(1-phenmethyl-4-Phenylpiperidine-4-yl)-tetrazolium-2-yl]-ethanamide)
To being equipped with magnetic stirrer, temperature regulator, condenser and N 23 liters of round-bottomed flasks of import add compound (2) (1-phenmethyl-4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines) (234.57g, 0734mol), dimethyl formamide (2.0L), salt of wormwood (121.8g, 0.881mol) and 2-bromoacetamide (101.32g, 0.734mol) (AldrichChemical Co., Milwaukee, Wisconsin).This reaction mixture is heated to 50 ℃ and at N 2Following overnight incubation.By LC/MS the analysis Indicator Reaction of reaction sample is finished.
Reaction mixture is cooled to room temperature and is introduced in the quick deionized water that stirs of 4.5L.Add ethyl acetate (2.5L) and collect formed throw out, it is dissolved in the ethyl acetate of about 6L subsequently by vacuum filtration.Separate the layer that is produced and reclaim ethyl acetate layer, evaporate so that underflow liquid to be provided through anhydrous sodium sulfate drying and by Rotary Evaporators.Described slurries grind with about 2L ether and collect suspended solids and dry by vacuum filtration, and the compound of 118.26g as light yellow solid (4) is provided.Same collect ether filtrate and vacuum concentration becomes mobile oil, by LC/MS analyze show contain compound (4) ( 1H NMR (MeOHd 4): δ 7.2-7.0 (m, 10H), 5.3 (s, 2H), 3.3 (s, 2H), 2.7 (m, 4H), 2.25 (m, 2H), 2.1 (m, 2H)).
5.3. embodiment 3: synthetic compound (5) (2-[5-(4-Phenylpiperidine-4-yl)-tetrazolium-2-yl]-ethanamide)
Reaction 5.3A:
Under argon shield, with compound (4) (2-[5-(1-phenmethyl-4-Phenylpiperidine-4-yl)-tetrazolium-2-yl]-ethanamide) (189.272g, 0.5mol), ethanol (3L), Glacial acetic acid (11.7mol), contain the catalyzer (10%Pd/C of 52.6g (the palladium powder on the activated carbon) (numbering E101 NE/W 10% Pd of 50% the water of having an appointment; DegussaCorporation, Parsippany, New Jersey) join in the 5 liter of three neck round-bottomed flask that is equipped with magnetic stirring bar.Under normal pressure, introduce hydrogen, and with the hydrogen purge flask to remove argon gas.Be reflected to stir under the hydrogen and spend the night.LC/MS analyzes Indicator Reaction and finishes.Filter by bed of diatomaceous earth with the argon purge reaction flask and under argon shield.Filter cake methanol wash, and the filtrate that concentrating under reduced pressure merged provide under high pressure further spissated viscous crude, to provide 148.51g as the foamy product.
Reaction 5.3B:
The mobile oil that contains compound (4) that will the ether filtrate evaporation by embodiment 5.2 provide (118.26g, 0.31mol), ethanol (1.65L), Glacial acetic acid (7.3mol) and containing had an appointment, and (10%Pd/C of 32.9g (the palladium powder on the activated carbon) (numbers E101NE/W 10%Pd for the palladium catalyst of 50% water; Degussa Corporation, Parsippany, New Jersey) place the single neck round-bottomed flask of the 3.0L that is equipped with magnetic stirring bar.React 5.3B, and the segregation product, as described in reaction 5.3A.After final enrichment step, it is the product of clarified liq that reaction 5.3B provides 71.95g.
The NMR analytical results of compound (5): 1H NMR (MeOHd 4): δ 7.2-7.0 (m, 10H), 5.5 (s, 2H), 3.2 (m, 2H), 2.85 (m, 4H), 2.3 (m, 2H).
5.4. embodiment 4: synthetic compound (6) (3,3-phenylbenzene-dihydro-furan-2-subunit)-dimethyl-brometo de amonio)
4-bromo-2 in chloroform, the 2-diphenyl butyric acid (100g, add in mechanical stirring suspension 0.313mol) triethylamine (65.2mL, 0.469mol), the dimethylamine THF solution of DMF (1mL) and 2M (160ml, 0.320mol).Reaction be cooled to-10 ℃ (dry ice, acetone bath) and slowly add oxalyl chloride in (dropwise) toluene (400mL) (60.6g 0.477mol), makes temperature of reaction remain on-5 ℃--between 10 ℃.Finish after the adding of oxalyl chloride, continued stirred reaction mixture 1.5 hours down 0 ℃ (ice/water-bath).Reaction mixture cools off after filtration, and the filtration cakes torrefaction that is reclaimed is spent the night, and obtains the 124.3g white solid, and it comprises mixture (6) and triethyl ammonium chloride, and it is used for next step without being further purified, as described in following examples 5.
5.5. embodiment 5: compound (7) (4-[4-(2-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-yl]-N, N-dimethyl-2,2-phenylbenzene-butyramide) synthetic
Reaction 5.5 (A):
With the solid chemical compound (5) of preparation in the foregoing description 5.3 (A) (2-[5-(4-phenyl-piperidin-4-yl)-tetrazolium-2-yl]-ethanamide) (71.95g, 0.25mol) (147.16g, 0.513mol), Na 2CO 3(127.8g), (187.48g is 0.541mol) in single neck round-bottomed flask of (as preparation as described in above-mentioned 5.4 joints) and DMF (about 2.5L) adding 5L for compound (6) ((3,3-phenylbenzene-dihydro-furan-2-subunit)-dimethyl-brometo de amonio).This reaction mixture is at N 2Under be heated to 100 ℃ and overnight incubation.Reaction finishes by reaction mixture being poured in the deionized water (about 6L), and with twice of ethyl acetate extraction of gained solution (each 2L).The combined ethyl acetate layer, through anhydrous sodium sulfate drying, and vacuum concentration, so that free-pouring oil to be provided.
Reaction 5.5 (B):
With compound (5) is clarified liq product, the Na of preparation in the above-mentioned reaction 5.3 (B) 2CO 3(62.5g), compound (6) ((3,3-phenylbenzene-dihydro-furan-2-subunit)-dimethyl-brometo de amonio) (91.69g, 0.26mol) and DMF (about 1L) add in single neck round-bottomed flask of 2L.This reaction mixture is at N 2Under be heated to 100 ℃ and overnight incubation.Reaction finishes by reaction mixture being poured in the deionized water (about 4L), and with twice of ethyl acetate extraction of gained mixture (each 1.5L).The combined ethyl acetate layer, through anhydrous sodium sulfate drying, and vacuum concentration, so that free-pouring oil to be provided.
Merging is also passed through the silica gel chromatography purifying by the unrestricted flow oil that reaction 5.5 (A) and 5.5 (B) provide, and obtains the compound (7) of 256.4g light yellow solid after concentrating.Silica gel chromatography utilizes the Biotage chromatographic column, and (Biotage, Charlottesville Virginia) carry out, and it is washed with ethyl acetate, use the solvent wash of being made up of 80% ethyl acetate, 10% ethanol and 10% triethylamine subsequently.The fraction that contains product utilizes thin-layer chromatography to identify.Product (256.4g) grinds in the acetonitrile (about 2.4L) of heat (boiling), and gained suspension cool overnight is to room temperature, and is freezing in ice bath subsequently.Collect solid by vacuum filtration, with the washing of cold (5 ℃) acetonitrile, dry air, vacuum-drying is subsequently spent the night, so that 193g to be provided the white solid compound (7) as unhindered amina.
The NMR analytical results of compound (7) is: ( 1H NMR (CDCl 3)): δ 7.65 (m, 8H), 7.55 (m, 6H), 7.42 (m, 1H), 5.85 (bs, 1H), 5.60 (bs, 2H), 5.30 (s, 2H), 2.98 (bs, 3H), 2.87 (bm, 4H), 2.20-2.45 (bm, 7H), 1.90-2.00 (bm, 4H).
To be converted into corresponding thionamic acid subsequently as the part of compounds (7) of unhindered amina.Compound (7) (100g) is dissolved in the 0.5L acetonitrile in the 2.0L round-bottomed flask.(AldrichChemical Co., Milwaukee Wisconsin) are dissolved in the acetonitrile solution that also under agitation adds compound (7) in the 50mL hot water (about 75 ℃) with monovalent (17.6g) thionamic acid.The gained solution of inclusion compound (7) and thionamic acid stir about 1 hour under 50 ℃ temperature is removed fine precipitation through filter paper filtering, and evaporation and vacuum-drying is subsequently spent the night.Dry substance is suspended in the acetonitrile of heat (boiling), is cooled to room temperature, freezing in ice-water bath subsequently.Collect solid by vacuum filtration, dry air with dry under high vacuum, provides the sulfamate as the 117.2g compound (7) of white solid.
The NMR analytical results of the sulfamate of compound (7) is: ( 1H NMR (DMSO d 6)): δ 7.80 (s, 1H), 7.45 (m, 5H), 7.32 (m, 8H), 7.20 (m, 3H), 5.38 (s, 2H), 2.88 (bs, 3H), 2.72 (bm, 2H), 2.30-2.60 (bm, 10H), 2.20 (bs, 3H), 2.06 (s, 3H).
5.6. embodiment 6: compound (9) (4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines) synthetic
Figure A20058000352201581
Compound (8) (4-cyano group-4-phenyl-piperidinium chloride ) (Acros Organics packs in being equipped with the 100mL round-bottomed flask of magnetic stirring bar, reflux exchanger/nitrogen inlet and temp probe, Morris Plains, New Jersey) (2.035g, 0.009mol), water (16mL), 1,4-two  alkane (9mL) and sodiumazide (1.16g, 0.018mol).(2.0g 0.009mol) and with 50% NaOH is adjusted to about 7 with pH value of solution to add zinc bromide.Heated the gained mixture 24 hours at about 90 ℃-Yue 100 ℃ of temperature range internal reflux.Collect formed white solid (" tetrazolium product " is compound (9)) in the reaction mixture and be directly used in subsequently step, this is disclosed in following 5.7 joints.Compound (9) characterizes by HPLC, and described HPLC utilizes the C18 chromatographic column of Phenomenex 150mm * 4.6mm, 5 micron grain sizes to carry out.Under 40 ℃, carry out stratographic analysis with the flow velocity of 1mL/min.UV by the 220nm place absorbs and monitors elutant.Utilize linear gradient to carry out elution 10 minutes, wherein the initial composition of moving phase is 90%A/10%B, moving phase finally consist of 10%A/90%B, wherein A is the phosphate buffered water of pH7.0, B is a methyl alcohol.This moving phase is formed and was kept 5 minutes, gets back to 90%A/10%B subsequently.Under this condition, 98% the purity that product compound (9) has 4.71 minutes retention time and utilizes that the HPLC area calculates.
5.7. embodiment 7: compound (6) ((3,3-phenylbenzene-dihydro-furan-2-subunit)-dimethyl-brometo de amonio) synthetic
This embodiment provides the method (than above embodiment 4) of the scheme as an alternative of synthetic compound (6).In the present embodiment disclosed method, all glasswares are dry before use.According to this method of scheme as an alternative, with the 4-bromo-2 in the toluene (20mL), (5g 14.8mmol) moves into and is equipped with in the three neck round-bottomed flasks of dry ice " prolong ", dimethyl amine gas feed and magnetic stirring bar 2-phenylbenzene chlorination butyric acid.This solution is cooled to 0 ℃-5 ℃, and adding triethylamine when keeping solution temperature to be 0 ℃-5 ℃ (3mL, 21.6mmol).Dimethyl amine gas is charged into the flask top, and keeping internal temperature simultaneously is 0 ℃-5 ℃.Reaction process is by to existing 4-bromo-2, and 2-phenylbenzene chlorination butyric acid is analyzed (passing through HPLC) reaction sample (sampling in per 5 minutes once) and monitored.In case 4-bromo-2,2-phenylbenzene chlorination butyric acid exhausts fully, then stops to add dimethyl amine gas to flask.Gained suspension is collected suspended solids by filtering subsequently 5 ℃ of extra down stirrings 30 minutes in the nitrogen purging bag glove.With the wet cake and the vacuum-drying of toluene wash gained, so that 4.75g to be provided white powder, it comprises the mixture of required product (mixture (6)) and Triethylammonium chloride, and it can be directly used in the reaction of following examples 8.
5.8. embodiment 8: compound (10) (N, N-dimethyl-2,2-phenylbenzene-4-[4-phenyl (2H-tetrazolium-5-yl)-piperidines-1-yl]-butyramide) synthetic
The tetrazolium product and the 15mL DMSO that form in the disclosed reaction in promptly above 5.6 joints of compound (9) (4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines) add the 25mL three neck round-bottomed flasks that are equipped with magnetic stirring bar, temp probe and nitrogen inlet.Stirred gained suspension about 5 minutes under the room temperature.Dropwise add in about 3 minutes DBU (2,3,4,6,7,8,9,10-octahydro-Mi Dingbing [1,2-α] azepine) (2.9mL, 2.952g, 0.0194mol).Stirred suspension is until obtaining solution (about 10 minutes).Separated into two parts adding compound (6) ((3,3-phenylbenzene-dihydro-furan-2-subunit)-dimethyl-brometo de amonio) in about 3 minutes (60% purity, 2.52g, 0.004mol).22 ℃ of following stirred reaction mixtures 140 minutes are used 10mL water termination reaction subsequently.The reaction mixture that is terminated is transferred to separating funnel with 30mL water, and with 20mL MTBE (methyl tertiary butyl ether) extraction, then with the extraction of 20mL isopropyl acetate.With dense HCl with the pH regulator of water to pH5, and make product (compound (10) (N, N-dimethyl-2,2-phenylbenzene-4-[4-phenyl (2H-tetrazolium-5-yl)-piperidines-1-yl]-butyramide)) extraction enter ethyl acetate (3 * 50mL).The organic phase that merge to reclaim, and be condensed into oil (" crude compound (10)), it is directly used in and forms compound (7), as described in following 5.9 joints.Compound (10) characterizes by HPLC, and described HPLC utilizes the C18 chromatographic column of Phenomenex 150mm * 4.6mm, 5 micron grain sizes to carry out.Under 40 ℃, carry out stratographic analysis with the flow velocity of 1mL/min.UV by the 220nm place absorbs and monitors elutant.Utilize linear gradient to carry out elution 10 minutes, wherein the initial composition of moving phase is 50%A/50%B, moving phase finally consist of 20%A/80%B, wherein A is the phosphate buffered water of pH7.0, B is a methyl alcohol.This moving phase is formed and was kept 6 minutes, changes into 50%A/50%B subsequently.Under this condition, 89% the purity that product compound (10) has 6.99 minutes retention time and utilizes that the HPLC area calculates.
5.9. embodiment 9: compound (7) (4-[4-(2-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-yl]-N, N-dimethyl-2,2-phenylbenzene-butyramide) synthetic
Figure A20058000352201611
With crude compound (10) (1.323g) (as formation as described in above 5.8 joints) be dissolved among the 15mL DMSO, and in the 50mL round-bottomed flask that is equipped with magnetic stirring bar, reflux exchanger/nitrogen inlet and temp probe of packing into.Add compound (11) (2-chlor(o)acetamide) (0.300g, 0.0032mol) (Aldrich Chemical Co., Milwaukee, Wisconsin) and salt of wormwood (1.1g 0.008mol), and heats the mixture of gained 4 hours under 60 ℃ of temperature.Add isopropyl acetate (30mL) and compound is transferred to separating funnel with 30mL water.With pH about 11 water with acetate Virahol extracting twice (extracting 30mL) at every turn.Reclaim organic extract, merge,,, and be condensed into oil through anhydrous sodium sulfate drying with the washing of 15mL saturated aqueous sodium chloride.Be dissolved in this oil in the 5.5mL methyl alcohol and stirred 30 minutes, during product (compound (7) (4-[4-(2-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-yl]-N, N-dimethyl-2,2-phenylbenzene-butyramide)) crystallization.By filtering the crystal (0.309g) of collecting compound (7).
The NMR analytical results of compound (7): (a) 1H NMR (CDCl 3, 600MHz): δ 1.96-2.01 (m, 4H), 2.29 (m, 4H), 2.37-2.40 (m, 3H), 2.74-2.76 (m, 4H), 2.84-3.02 (m, 3H), 5.27 (s, 2H), 5.66 (s, 1H), 5.86 (s, 1H), 7.15 (m, 1H), 7.24-7.27 (m, 6H), 7.34-7.38 (m, 8H); (b) 13C NMR (CDCl 3, 150.9MHz): 35.43,41.58,42.37,50.76,55.20,56.02,59.86,126.17,126.84,126.92,128.29,128.59,128.75,140.96,165.76,173.73.
Compound (7) characterizes by HPLC, and described HPLC utilizes the C18 chromatographic column of Phenomenex 150mm * 4.6mm, 5 micron grain sizes to carry out.Under 40 ℃, carry out stratographic analysis with the flow velocity of 1mL/min.UV by the 220nm place absorbs and monitors elutant.Utilize linear gradient to carry out elution 10 minutes, wherein the initial composition of moving phase is 50%A/50%B, moving phase finally consist of 20%A/80%B, wherein A is the phosphate buffered water of pH7.0, B is a methyl alcohol.This moving phase is formed and was kept 6 minutes, changes into 50%A/50%B subsequently.Under this condition, 98% the purity that product compound (7) has 10.312 minutes retention time and utilizes that the HPLC area calculates.
5.10. embodiment 10: compound (14) (4-phenyl-4-(2H-tetrazolium-5-yl) piperidines-1-carboxylic acid tert-butyl ester) synthetic
Figure A20058000352201621
In first example, compound (14) is synthetic as follows: with compound (9) hydrochloric acid (4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines) (can be formed on the salt of the tetrazolium product in the disclosed reaction of above 5.6 joints) (50g, 145mmol) under agitation be suspended in (12.85g in the aqueous sodium hydroxide solution, 321.2mmol, in 200mL water).Adding heavy carbonic di tert butyl carbonate (compound (12)) also stirs the mixture fast.Temperature of reaction at first rose to 40 ℃ in 5 minutes, descend subsequently.Mixture cools off in water-bath, at room temperature stirs subsequently and spends the night.Mixture distributes between ethyl acetate (1L) and acetic acid aqueous solution (100mL in the 1L water), separates organic phase.Water is further used ethyl acetate (1L) extraction, and with the organic phase vacuum-evaporation drying that merges so that required product-foam-like compound (14) to be provided, make it leave standstill crystallization.Use hexane subsequently: ether (1: 1) is grinding product (200mL).
In second example, synthetic compound in fairly large reaction (14) is as follows: with compound (9) (4-phenyl-4-(2H-tetrazolium-5-yl)-piperidines hydrochloric acid zinc chloride complex compound) (100g, 292.06mmol) be suspended in (15.42g in the aqueous sodium hydroxide solution of 400mL water, 642.25mmol), stirred 10 minutes.Add compound (12) (heavy carbonic di tert butyl carbonate) (70.07g, (200mL) solution of acetone 321.25mmol) and vigorous stirring mixture 4h.Mixture was stirred 15 minutes with ethyl acetate (250mL) dilution and continuation, with some viscous solid on the dissolving walls of beaker.Mixture distributes between ethyl acetate (1000mL) and 0.5M thionamic acid solution (1000mL), separates organic phase.Organic phase is washed with 0.5M thionamic acid solution (1000mL) and water (1000mL).Water is stripped with ethyl acetate (1000mL), and the organic phase drying (MgSO4) and the vacuum evaporating solvent that merge is extremely dry to obtain white solid.It is ground to obtain the compound (14) (80.5g, 88%) as white solid, its m.p.=184.5-186 ℃ with hexane (500mL); TLC SiO 2, EtOAc Rf=0.56; δ H{400MHz, CDCl 37.29-7.18 (5H, m), 3.90 (2H, m), 3.25-2.70 (4H, m), 2.40-2.15 (2H, m), 1.40 (9H, s); LC: measure purity 100% by DAD; MS:[M+Na] +=352.2/353.1.
5.11. embodiment 11: compound (22) (4-phenyl-4-(2-(2-phenyl third-1-yl)-2H-tetrazolium-5-yl) piperidines-1-carboxylic acid tert-butyl ester) synthetic
With compound (20) (5-phenmethyl-2-(2-phenyl third-2-yl)-2H-tetrazolium) (1g; 3.59mmol) be dissolved in the diethyl ether (80mL), and at-15 ℃ approximately--20 ℃ of temperature (ice/water/NH 4The Cl bath) adds n-Butyl Lithium (4.5mL down; 7.18mmol).In 5 minutes, dropwise add compound (21) (two (2-chloroethyl) t-butyl carbamate) (0.95g; 3.95mmol) diethyl ether (10mL) solution, stirred the mixture 30 minutes at-15 ℃ afterwards, notice color change during this period, become light yellow from garnet.The mixture insulation to-10 ℃, is warming up to room temperature afterwards.Use 50mL NH 4Cl aqueous solution termination reaction.Separating obtained layer and through MgSO 4Drying, concentrate drying subsequently.Desciccate is suspended,, merge the fraction that contains product and also concentrate, obtain 1g compound (22) through chromatographic separation.
5.12. embodiment 12: the preparation of compound (15) (4-(2-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-carboxylic acid tert-butyl ester)
With compound (14) (4-phenyl-4-(2H-tetrazolium-5-yl) piperidines-1-carboxylic acid tert-butyl ester) (20g, 60.7mmol), sodium iodide (10.85g, 72.9mmol), yellow soda ash (7.73g, 72.9mmol) and compound (11) (2-chlor(o)acetamide) (5.85g, 62.52mmol) under agitation in acetone (100ml) together 40 ℃ the heating 48 hours.The refrigerative mixture distributes and separates organic phase between ethyl acetate (500mL) and saturated sodium bicarbonate solution (500mL).With water usefulness ethyl acetate (500mL) reextraction and with the organic phase drying (MgSO that merges 4), vacuum evaporating solvent stays white solid (22.9g, 95%) to drying.This solid is dissolved in the hot ethyl acetate (100mL).Add toluene (400mL) and mixture is refluxed.The mixture filtered while hot to remove insoluble impurities, was slowly cooled to room temperature through stirring subsequently in 2 hours.Mixture is filtered and wash, to obtain compound (15) (16.3g, 80%), m.p.=156-157.5 ℃ with hexane (100mL); δ H{400MHz, CDCl 37.35-7.18 (5H, m), 5.85 (1H, bs), 5.62 (1H, bs), 5.31 (2H, s), 3.96 (2H, bs), 2.96 (2H, bs), 2.81 (2H, bd, J=13.3Hz), 2.25 (2H, bt, H=13.3Hz), 1.45 (9H, s); TLC SiO2 (EtOAc: hexane, 1: 1) Rf=0.18 detects UV; LC: measure purity 100% by DAD; MS:[M+Na] +=409.2.
Product is at CDCl 3In 1H NMR does not detect any isomer products compound (27):
Compound (27)
The method of a kind of segregation compound (27) is described in following 5.13 joints (embodiment 13).
5.13. embodiment 13: the preparation of compound (27) (4-(1-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-carboxylic acid tert-butyl ester)
With the thick alkylation tetrazolium of a collection of 300g (usually as 5.12 joint embodiment 12 as described in preparation) from above-mentioned ethyl acetate: recrystallization the solution of toluene (1: 4); obtain 255g compound (15) (4-(2-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-carboxylic acid tert-butyl ester) altogether, productive rate is 73%.Mother liquor vacuum concentration drying is obtained light yellow solid.Add ethyl acetate (700mL) and stirring heating mixture to refluxing, filtered while hot obtain as white solid compound (27) (10.5g), utilize 1H NMR and LC/MS purity assay＞98%.Its recrystallization from methyl alcohol is obtained compound (27) (8.28g), utilize 1H NMR and LC/MS purity assay＞99.9%.δ H{400MHz, (CD 3) 2SO}7.67 (1H, bs), 7.47 (1H, bs), 7.41-7.28 (3H, m), 7.15 (2H, m), 4.53 (2H, s), 3.80 (2H, m), 3.10 (2H, m), 2.43 (2H, m), 2.10 (2H, m), 1.40 (9H, s); LC: measure purity 100% by DAD; MS:[M+Na] +=409.2.
5.14. embodiment 14: the preparation of compound (5) (2-[5-(4-phenyl-piperidin-4-yl)-tetrazolium-2-yl]-ethanamide)
Figure A20058000352201652
(130g 336.4mmol) is suspended in the exsiccant methylene dichloride (500mL) with compound (15) (4-(2-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-carboxylic acid tert-butyl ester).Adding trifluoroacetic acid (150mL) also at room temperature stirred the mixture 2 hours.Solvent removed in vacuo is also poured residuum in the water (800mL) into, alkalizes to pH9 with salt of wormwood.At this stage filtering mixt to remove some dark matter particulates.With colourless filtrate with the aqueous sodium hydroxide solution of 1M further alkalization to＞pH12 and add the kind crystalline substance of compound (5).With frozen water cooling and stirring 1 hour and filter, obtain white crystalline solid, with its under high vacuum through drierite ze in 70 ℃ of dryings 18 hours, obtain the compound (5) of white solid, m.p.=155-157 ℃.The vacuum concentration filter liquor is regulated pH to＞12 to about 300mL and with the sodium hydroxide of 1M.It is brilliant and with frozen water cooling and stirring 1 hour to add the kind of required product, filter and obtain other compound (5) (12.2g), its high vacuum and 70 ℃ dry down as before.The overall yield of compound (5) is (82.2g, 85.6%); δ H400MHz, d6DMSO}7.83 (1H, bs), 7.46 (1H, bs), 7.32-7.16 (5H, m), 5.38 (2H, s), 2.91 (2H, bd, J=12.3Hz), 2.61 (2H, bd, H=12.3Hz), 2.52 (2H, m), 2.10 (2H, bt, J=9.2Hz); LC:DAD measures purity 100%; MS:[M+H] +=287.2.
5.15. embodiment 15: the replacement scheme of preparation compound (6) (dimethyl (3,3-phenylbenzene-2-furylidene) brometo de amonio)
Except above 5.4 joints and 5.7 joint disclosed methods, compound (6) can also be prepared as follows: with 4-bromo-2, (50g 156.7mmol) is suspended in the methylene dichloride (250mL) the 2-diphenyl butyric acid.(14.4mL, reflux is 2 hours 164.5mmol) and under argon gas to add oxalyl chloride.The response estimator time removes solvent with final vacuum when gas release stops, and to obtain thick acyl chlorides, it uses at once.(19.9g 188.04mmol) is dissolved in the water (200mL), and solution is cooled to-5 ℃ (ice-acetone) with yellow soda ash.(24mL 188.04mmol), adds toluene (200mL) to the dimethyl amine aqueous solution of adding 40%w/w 7.9M subsequently.During adding, maintain the temperature at below 0 ℃ during the acyl chlorides in the toluene (250mL) added in 15 minutes and adding, and under this temperature with mixture restir 1 hour.Separate organic layer (discarding) and use methylene dichloride (5 * 500mL) aqueous layer extracted, dry (MgSO to remove impurity 4) and vacuum evaporating solvent, to obtain the solid of rice white, it stopped 20 minutes down in 50 ℃ in Rotary Evaporators.Solid is ground compound (6) (37.5g, 69.4%) to obtain white solid with ethyl acetate (250mL).δH{400MHz，CDCl 3}7.56-7.36(10H，m)，4.86(2H，t，J＝7.0Hz)，3.82(3H，s)，3.47(2H，t，J＝7.0Hz)，2.96(3H，s)。
5.16. embodiment 16: compound (7) (4-[4-(2-carbamyl ylmethyl-2H-tetrazolium-5-yl)-4-phenyl-piperidines-1-yl]-N, N-dimethyl-2,2-phenylbenzene-butyramide) preparation
Figure A20058000352201671
With compound (5) (as 2-[5-(4-phenyl-piperidin-4-yl)-tetrazolium-2-yl]-ethanamide trifluoroacetate) (1g, 2.5mmol), compound (6) ((3,3-phenylbenzene-dihydro-furan-2-subunit)-and dimethyl-brometo de amonio): Triethylammonium chloride (1: 1 mixture) (1.33g, 2.75mmol) and yellow soda ash (0.795g, 7.5mmol) be suspended in the dry acetone (20mL) and be heated to 50 ℃ 18 hours.The refrigerative compound is distributed and separates organic phase between ethyl acetate (100mL) and 8% sodium bicarbonate aqueous solution (100mL), dry (MgSO 4) and evaporating solvent is extremely dry in a vacuum, to obtain yellow glue.To the residue ethyl acetate: methyl alcohol: flash chromatography is carried out in ammonia (100: 10: 10) elution, obtains foam.Be dissolved in it in acetonitrile (25mL) and make its slow crystallization.Filtering mixt obtains the compound (7) (930mg, 67%) of white solid.δH{400MHz，d6CDCl 3}7.40-7.13(15H，m)，5.89(1H，bs)，5.68(1H，bs)，5.27(2H，s)，2.96(3H，bs)，2.75(4H，m)，2.40(2H，m)，2.30(5H，m)，2.09-1.93(4H，m)，1.72(4H，m)；LC：DAD?100％；MS：[M+Na] +＝552.3/553.3。
5.17. embodiment 17: compound (18) (5-phenmethyl-1-H-tetrazolium) synthetic
With compound (17) (phenmethyl prussiate) (49mL, 425mmol), NaN 3(33.15g, 510mmol) and Triethylammonium chloride (70g 510mmol) is suspended in the dry acetone of 800mL.Mixture is being warming up to 100 ℃ and stirred 16 hours under this temperature under the argon gas.When cooling, add the 800mL deionized water.Remove water layer and utilize dense HCl to be acidified to pH＜4.Use 3 * 500 ethyl acetate extraction water layer subsequently.Combined ethyl acetate layer and through the MgSO4 drying filters and concentrate drying, obtains the compound (18) of white solid.Productive rate 100%; δ H{400MHz, CDCl 37.28 (5H, m), 4.35 (2H, s).LC/MS=(100%, tr=2.234 minute), m/z=161.0[M+H] +Calculated value: 160.0.
5.18. embodiment 18: compound (20) (5-phenmethyl-2-(1-methyl isophthalic acid-phenyl-ethyl)-2H-tetrazolium) synthetic
Figure A20058000352201681
With phenmethyl tetrazole compound (18) (50g, 310mmol) and trichoroacetic acid(TCA) (116.95g 713mmol) is suspended in the CHCl of 500mL 3In.Dropwise add compound (19) (alpha-methyl styrene) (40.3mL, 50mLCHCl 310mmol) with its stirring and in 10 minutes 3Solution.Stir after 1 hour, add the 500mL10%KOH aqueous solution.Separate organic layer, through MgSO 4Drying is filtered and be concentrated into to drying.Crude product is dissolved in the pure hexane and by the silicon-dioxide plug filters, until removing excessive compound (9) (alpha-methyl styrene) with hexane wash.Subsequently, the washing of the hexane solution of the ethyl acetate with 50% obtains the required tetrazolium that is protected, and obtains compound (20) behind the concentrate drying.Obtain the 81.87g product compound (20) of colorless oil.Productive rate 95%; δ H{400MHz, CDCl 3}: 7.30 (8H, m), 7.08 (2H, d, J=8Hz).LC/MS=(100%, tr=4.889 minute), m/z=301.1[M+H] +Calculated value: 278.36.
5.19. embodiment 19: compound (24) (4-phenyl-4-(2-(2-phenyl third-2-yl)-2H-tetrazolium-5-yl)-1-tolysulfonyl phenylpiperidines) synthetic
Figure A20058000352201691
(20g 71.85mmol) is dissolved in the dry diethyl ether of 400mL with compound (20) (5-phenmethyl-2-(2-phenyl third-2-yl)-2H-tetrazolium).It is cooled to-15 ℃ under Ar.In 10 minutes, dropwise add 1.6M the n-Butyl Lithium hexane solution (99mL, 158.07mmol).This mixture was stirred 0.5 hour.In 10 minutes, dropwise add compound (23) (N-p-toluenesulfonyl-two-(2-chloroethyl) amine) (25.5g, 100mL diethyl ether solution 86.22mmol).With this mixture heating up to room temperature and stirred 16 hours.With the saturated NH of 400mL 4Cl aqueous solution termination reaction.Add ethyl acetate (100mL) and separating layer.Drying is filtered and be concentrated into to organic phase through the MgSO4 drying.A small amount of compound (24) is passed through to use the chromatogram purification of EtOAc/ hexane (1: 4) elution.White solid.δH{400MHz，CDCl 3}：7.58(2H，d，J＝8Hz)，7.19-7.29(10H，m)，6.82(2H，d，J＝8Hz)，3.73(2H，m)，2.89(2H，m)，2.44(3H，s)，2.37(4H，m)，2.01(6H，s)。LC/MS=(100%, tr=3.742 minute), m/z=524.3[M+H] +Calculated value: 501.66.Remaining crude compound (24) is used for next step (5.20 joints, embodiment 20).
5.20. embodiment 20: compound (25) (4-phenyl-4-(2H-tetrazolium-5-yl)-1-(toluene-4-alkylsulfonyl)-piperidines) synthetic
Figure A20058000352201701
Crude compound (24) is dissolved in the 50mL dehydrated alcohol.To wherein add potassium formiate (36g, 431.1mmol) and 10%Pd/C (13g).Reflux and stirred 4 hours down.Be concentrated into drying subsequently with mixture process diatomite filtration, and with filtrate, obtain crude compound (25).This material is distributed between water and ethyl acetate.The separating ethyl acetate layer also washes with water again.Merge moisture fraction and be acidified to pH＜3 (HCl concentration).Use the ethyl acetate extraction water layer, separate subsequently, dry (MgSO4) also is concentrated into drying, obtains pure substantially compound (25), and it can use without being further purified.Obtain 25g white foam shape product compound (25).δH{400MHz，CDCl 3}：7.51(2H，d，J＝8Hz)，7.10-7.29(7H，m)，3.59(2H，m)，2.69(2H，m)，2.20-2.38(7H，m)，2.37(4H，m)。LC/MS=(85%, tr=2.730 minute), m/z=384.1[M+H] +Calculated value: 383.48.
5.21. embodiment 21: compound (26) (2-{5-[4-phenyl-1-(toluene-4-alkylsulfonyl)-piperidin-4-yl] tetrazolium-2-yl }-ethanamide) synthetic
Figure A20058000352201702
Crude compound (25) (3.5g) is dissolved in the 100mL acetone.To wherein adding NaI (1.2 equivalent), K 2CO 3(1.2 equivalent) and compound (11) (2-chlor(o)acetamide) (1 equivalent).Stirring also is heated to 40 ℃, continues 4 hours.This mixture is distributed between deionized water and ethyl acetate.Separating layer also makes organic phase through MgSO 4Drying is filtered and be concentrated into to drying.Add ethyl acetate and make the crude product recrystallization, obtain the compound (26) of 3.7g white crystalline solid.Productive rate 89%.δ H{400MHz，CDCl 3}：7.61(2H，d，J＝8Hz)，7.22(7H，m)，5.91(1H，bs)，5.72(1H，bs)，5.20(2H，s)，3.69(2H，m)，2.85(2H，m)，2.53(2H，m)，2.40(5H，m)。LC/MS=(100%, tr=2.936 minute), m/z=441.1[M+H] +Calculated value: 440.16.
5.22. embodiment 22: compound (5) (2-[5-(4-phenyl-piperidin-4-yl)-tetrazolium-2-yl]-ethanamide) synthetic
Figure A20058000352201711
(3.7g 8.39mmol) is suspended in the 60mL vitriol oil with compound (26).Be heated to 115 ℃ and continue 8 hours.Mixture is cooled to room temperature and under 10 ℃, high degree of agitation, dropwise is added among the 6M NaOH of 400mL.LC/MS shows does not have initiator and the peak that demonstrates corresponding to tosic acid and desired product compound (5).(10 * 500mL) extract with ethyl acetate with product.Organic phase is concentrated into drying, obtains 2.2g crude compound (5).
The invention is not restricted to the scope of disclosed particular among the embodiment, described embodiment is used to illustrate aspects more of the present invention.Therefore, any embodiment that is equivalent to embodiment disclosed herein on the function all within the scope of the present invention.In fact, except that shown in this paper and described, be conspicuous to those skilled in the art and these change within the scope of the appended claims for various changes of the present invention.
A large amount of reference of being quoted are incorporated its full content into this paper by reference.

Claims (83)

1. the compound of chemical formula (2)
Figure A2005800035220002C1
Or its salt.
2. the compound of chemical formula (4)
Or its salt.
3. the compound of chemical formula (9)
Figure A2005800035220002C3
Or its salt.
4. the compound of chemical formula (5)
Or its salt.
5. composition comprises sodiumazide, zinc salt, contains the solvent of polar proton inert solvent and the compound of chemical formula (1)
Figure A2005800035220003C2
6. the composition of claim 5, wherein polar proton inert solvent is selected from N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO) and combination thereof.
7. the composition of claim 5, wherein said solvent comprises the mixture of N-Methyl pyrrolidone and water.
8. the composition of claim 7, it is about 10: 1 N-Methyl pyrrolidone that wherein said mixture comprises ratio: the N-Methyl pyrrolidone of water and water.
9. the composition of claim 5, wherein said zinc salt is selected from ZnBr 2, ZnCl 2And ZnI 2, Zn (ClO 4) 2And Zn (CF 3SO 3) 2And combination.
10. composition comprises polar proton inert solvent, non-nucleophilic base, has according to the alkylating reagent of the structure of Formulae II and the compound of chemical formula (2),
Figure A2005800035220003C3
Chemical formula (II)
Wherein, n is the integer of 1-4, R 3And R 4Independent separately be H or-(C 1-C 4And X alkyl), 1For-Br ,-Cl or-I,
Figure A2005800035220004C1
11. the composition of claim 10, wherein polar proton inert solvent is selected from N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) and combination thereof.
12. the composition of claim 10, wherein non-nucleophilic base is selected from triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate and two or more mixture thereof.
13. the composition of claim 10, wherein X 1Be Br, n=1, R 3And R 4The H that respectively does for oneself, non-nucleophilic base is a salt of wormwood, polar proton inert solvent is a dimethyl formamide.
14. composition comprises the compound of chemical formula (5)
Figure A2005800035220004C2
And the compound of chemical formula (6)
15. the composition of claim 14 also comprises polar proton inert solvent and non-nucleophilic base.
16. the composition of claim 15, wherein polar proton inert solvent is selected from N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) and combination thereof.
17. the composition of claim 16, wherein polar proton inert solvent is a dimethyl formamide.
18. the composition of claim 15, wherein non-nucleophilic base is selected from triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate and two or more combination thereof.
19. the composition of claim 18, wherein non-nucleophilic base is a yellow soda ash.
20. the method for the compound of preparation chemical formula (2),
Be included in the compound that makes chemical formula (1) in the solvent that contains polar proton inert solvent
Figure A2005800035220005C2
React in the presence of zinc salt with sodiumazide, to generate compound (2).
21. the method for claim 20, wherein zinc salt is selected from ZnBr 2, ZnCl 2And ZnI 2, Zn (ClO 4) 2And Zn (CF 3SO 3) 2
22. the method for claim 20, wherein polar proton inert solvent is selected from N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE and dimethyl sulfoxide (DMSO) and combination thereof.
23. the method for claim 22, wherein polar proton inert solvent is a N-Methyl pyrrolidone.
24. the method for claim 20, wherein said solvent comprises the mixture of N-Methyl pyrrolidone and water.
25. it is about 10 that the method for claim 24, wherein said solvent comprise ratio: the 1N-methyl-2-pyrrolidone: the N-Methyl pyrrolidone of water and the mixture of water.
26. the method for the compound of preparation chemical formula (4),
Figure A2005800035220005C3
Be included in the compound that makes chemical formula (2) in the solvent that contains polar proton inert solvent
Figure A2005800035220006C1
Compound with Formula I X
Figure A2005800035220006C2
Wherein X is selected from Br, Cl or I,
Formula I X
Reaction in the presence of non-nucleophilic base is to generate compound (4).
27. the method for claim 26, wherein polar proton inert solvent is selected from N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) and combination thereof.
28. the method for claim 26, wherein polar proton inert solvent is a dimethyl formamide.
29. the method for claim 26, wherein non-nucleophilic base is selected from triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate and two or more combination thereof.
30. the method for claim 29, wherein non-nucleophilic base is a salt of wormwood.
31. prepare the method for compound (7),
Figure A2005800035220006C3
Be included in the compound that makes chemical formula (5) in the solvent that contains polar proton inert solvent
Compound with chemical formula (6)
Figure A2005800035220007C2
Reaction in the presence of non-nucleophilic base is to generate compound (7).
32. the method for claim 31, wherein polar proton inert solvent is selected from N-Methyl pyrrolidone, dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) and combination thereof.
33. the method for claim 32, wherein polar proton inert solvent is a dimethyl formamide.
34. the method for claim 32, wherein non-nucleophilic base is selected from triethylamine, diisopropylethylamine, yellow soda ash, salt of wormwood, cesium carbonate and two or more combination thereof.
35. the method for claim 34, wherein non-nucleophilic base is a yellow soda ash.
36. prepare the method for compound (7),
Comprise that (a) makes the compound of chemical formula (2) in containing the solvent of polar proton inert solvent
Compound with Formula I X Wherein X is selected from Br, Cl and I,
Formula I X
Reaction in the presence of non-nucleophilic base is to generate the compound of chemical formula (4)
(b) make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided
With
(c) compound with chemical formula (5) is converted into compound 7.
37. prepare the method for compound (7),
Figure A2005800035220008C4
Comprise that (a) makes the compound of chemical formula (2) in containing the solvent of polar proton inert solvent
Figure A2005800035220009C1
Compound with Formula I X Wherein X is selected from Br, Cl and I,
Formula I X
Reaction in the presence of non-nucleophilic base is to generate the compound of chemical formula (4)
Figure A2005800035220009C3
With
(b) make the compound of chemical formula (4) be converted into compound (7).
38. prepare the method for compound (7),
Figure A2005800035220009C4
Comprise that (a) makes the compound of chemical formula (1)
Figure A2005800035220010C1
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided
With
(b) make the compound of chemical formula (2) be converted into compound (7).
39. prepare the method for compound (7),
Figure A2005800035220010C3
Comprise that (a) makes the compound of chemical formula (1)
Figure A2005800035220010C4
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided
(b) make the compound of chemical formula (2) and the compound of Formula I X
Formula I X
Wherein X is selected from Br, Cl and I, and reaction in the presence of non-nucleophilic base is to generate the compound of chemical formula (4)
(c) make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided
With
(d) make the compound of chemical formula (5) and the compound of chemical formula (6)
Figure A2005800035220012C1
Reaction forms compound (7) thus in the presence of non-nucleophilic base
40. prepare the method for compound (7),
Figure A2005800035220012C3
Comprise that (a) in the solvent that contains water and two  alkylating mixtures, makes the compound of chemical formula (8)
With sodiumazide and zinc salt reaction, so that the compound of chemical formula (9) to be provided
Figure A2005800035220013C1
With
(b) make the compound of chemical formula (9) be converted into compound (7).
41. prepare the method for compound (7),
Figure A2005800035220013C2
Comprise that (a) in containing the solvent of polar proton inert solvent, makes the compound of chemical formula (9)
Figure A2005800035220013C3
Compound with chemical formula (6)
Figure A2005800035220013C4
In the presence of non-nucleophilic base, react, so that the compound of chemical formula (10) to be provided
Figure A2005800035220014C1
With
(b) make the compound of chemical formula (10) be converted into compound (7).
42. prepare the method for compound (7),
Comprise: (a) in the solvent that contains water and two  alkylating mixtures, make the compound of chemical formula (8)
Figure A2005800035220014C3
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (9) to be provided
(b) make the compound of chemical formula (9) and the compound of chemical formula (6)
Reaction in the presence of non-nucleophilic base is to provide the compound of chemical formula (10)
Figure A2005800035220015C2
With
(c) make the compound of chemical formula (10) and the compound of Formula I X
Figure A2005800035220015C3
Reaction,
Formula I X
Wherein X is selected from Br, Cl and I, forms compound (7) thus
Figure A2005800035220015C4
43. composition comprises the compound of sodiumazide, zinc salt and chemical formula (8)
44. composition comprises the compound of chemical formula (9)
The compound of chemical formula (6)
Figure A2005800035220016C2
And non-nucleophilic base.
45. prepare the method for compound (7),
Figure A2005800035220016C3
Comprise: the compound that (a) makes chemical formula (4)
Figure A2005800035220016C4
Debenzylation in the presence of hydrogen and noble metal catalyst is to provide the compound of chemical formula (5)
Figure A2005800035220016C5
With
(b) make the compound of chemical formula (5) and the compound of chemical formula (6)
Figure A2005800035220017C1
In the presence of non-nucleophilic base, react, form compound (7) thus
46. prepare the method for compound (7),
Figure A2005800035220017C3
Comprise: the compound that (a) makes chemical formula (2)
Figure A2005800035220017C4
Compound with Formula I X
Figure A2005800035220018C1
Wherein X is selected from Br, Cl and I,
Formula I X
Reaction in the presence of non-nucleophilic base is to generate the compound of chemical formula (4)
Figure A2005800035220018C2
(b) make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided
Figure A2005800035220018C3
With
(c) make the compound of chemical formula (5) and the compound of chemical formula (6)
In the presence of non-nucleophilic base, react, form compound (7) thus
Figure A2005800035220019C1
47. prepare the method for compound (7),
Figure A2005800035220019C2
Comprise: the compound that (a) makes chemical formula (10)
Compound with Formula I X Reaction, wherein X is selected from Br, Cl and I,
Formula I X
Form compound (7) thus
Figure A2005800035220020C1
48. prepare the method for compound (7),
Figure A2005800035220020C2
Comprise: the compound that (a) makes chemical formula (9)
Figure A2005800035220020C3
Compound with chemical formula (6)
In the presence of non-nucleophilic base, react, so that the compound of chemical formula (10) to be provided
With
(b) make the compound of chemical formula (10) and the compound of Formula I X
Figure A2005800035220021C2
Reaction,
Formula I X
Wherein X is selected from Br, Cl and I, forms compound (7) thus
Figure A2005800035220021C3
49. the method for the compound of preparation chemical formula (5),
Comprise: the compound that (a) makes chemical formula (2)
Compound with Formula I X Wherein X is selected from Br, Cl and I,
Formula I X
Reaction in the presence of non-nucleophilic base is to provide the compound of chemical formula (4)
With
(b) make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided
50. prepare method according to the compound of chemical formula (5),
Figure A2005800035220023C1
Comprise:
(a) make the compound of chemical formula (1)
Figure A2005800035220023C2
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided
Figure A2005800035220023C3
(b) make the compound of chemical formula (2) and the compound of Formula I X
Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl and I, so that the compound of chemical formula (4) to be provided
Figure A2005800035220024C1
With
(c) make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (4), so that the compound of chemical formula (5) to be provided
51. the method for the compound of preparation chemical formula (9),
Figure A2005800035220024C3
Comprise:
(a) make the compound of chemical formula (2)
Debenzylation in the presence of hydrogen and noble metal catalyst forms the compound of chemical formula (9) thus.
52. prepare method according to the compound of chemical formula (9),
Comprise:
(a) in containing the solvent of polar proton inert solvent, make the compound of chemical formula (1)
Figure A2005800035220025C2
React in the presence of zinc salt with sodiumazide, to generate the compound of chemical formula (2)
Figure A2005800035220025C3
With
(b) make compound debenzylation in the presence of hydrogen and noble metal catalyst of chemical formula (2), form the compound of chemical formula (9) thus.
53. prepare method according to the compound of chemical formula (9),
Figure A2005800035220025C4
Be included in the solvent that contains polar proton inert solvent, make the compound of chemical formula (8)
Figure A2005800035220026C1
With sodiumazide and zinc salt reaction, form the compound of chemical formula (9) thus.
54. the method for claim 53, wherein solvent comprises the mixture of two  alkane and water.
55. the method for the compound of preparation chemical formula (4),
Comprise:
(a) make the compound of chemical formula (1)
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (2) to be provided
Figure A2005800035220026C4
With
(b) make the compound of chemical formula (2) and the compound of Formula I X
Figure A2005800035220027C1
Formula I X
React in the solvent that is containing polar proton inert solvent in the presence of the non-nucleophilic base, wherein X is selected from Br, Cl and I, to produce compound (4).
56. the method for the compound of preparation chemical formula (5),
Comprise the compound that makes chemical formula (4)
Debenzylation in the presence of hydrogen and noble metal catalyst is to provide the compound of chemical formula (5).
57. the compound of chemical formula (20)
Or its salt.
58. the compound of chemical formula (25)
Figure A2005800035220028C1
Or its salt.
59. the compound of chemical formula XII
Figure A2005800035220028C2
Or its salt, wherein R 5Be selected from
Figure A2005800035220028C3
With
Figure A2005800035220028C4
60. the compound of chemical formula XIV
Figure A2005800035220028C5
Or its salt, wherein n is the integer of 1-4, R 3And R 4Independent separately be hydrogen or-(C 1-C 4Alkyl), R 5Be selected from
Figure A2005800035220029C1
With
Figure A2005800035220029C2
61. the compound of claim 60, wherein n is 1, R 3And R 4Be hydrogen, R 5For
Figure A2005800035220029C3
62. the compound of claim 60, wherein n is 1, R 3And R 4Be hydrogen, R 5For
Figure A2005800035220029C4
63. the method for the compound of preparation chemical formula (15),
Comprise the compound that makes chemical formula (14)
Compound with Formula I X
Figure A2005800035220029C7
Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate compound (15).
64. the method for the compound of preparation chemical formula (15) comprises making compound (20)
With compound (21)
Figure A2005800035220030C2
Reaction is to generate the compound of chemical formula (22)
Figure A2005800035220030C3
Make compound (22) go protection, so that the compound of chemical formula (14) to be provided
With
Make the compound of chemical formula (14) and the compound of Formula I X
Figure A2005800035220030C5
Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate compound (15).
65. the method for the compound of preparation chemical formula (15) comprises the compound that makes chemical formula (8)
Figure A2005800035220031C1
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (9) to be provided
Figure A2005800035220031C2
Make the compound of chemical formula (9) and the compound of chemical formula (12)
Reaction is to generate the compound of chemical formula (14)
Figure A2005800035220031C4
With
Make the compound of chemical formula (14) and the compound of Formula I X
Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl and I, to generate compound (15).
66. the method for the compound of preparation chemical formula (26),
Figure A2005800035220032C1
Comprise the compound that makes chemical formula (25)
Figure A2005800035220032C2
Compound with Formula I X Reaction in the presence of non-nucleophilic base,
Formula I X
Wherein X is selected from Br, Cl or I, to generate compound (26).
67. the method for the compound of preparation chemical formula (26),
Comprise the compound that makes chemical formula (20)
Compound with chemical formula (23)
Figure A2005800035220033C2
Reaction is to generate the compound of chemical formula (24)
Make compound (24) go protection, so that the compound of chemical formula (25) to be provided
Figure A2005800035220033C4
With
Make the compound of chemical formula (25) and the compound of Formula I X
Figure A2005800035220033C5
Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate compound (26).
68. the method for the compound of preparation chemical formula (20) comprises the compound that makes chemical formula (18)
Compound with chemical formula (19)
Figure A2005800035220034C2
Reaction is to generate the compound of chemical formula (20).
69. the method for the compound of preparation chemical formula (20) comprises the compound that makes chemical formula (17)
Figure A2005800035220034C3
React in the presence of zinc salt with sodiumazide, so that the compound of chemical formula (18) to be provided
Figure A2005800035220034C4
With
Make the compound of chemical formula (18) and the compound of chemical formula (19)
Figure A2005800035220034C5
Reaction is to generate the compound of chemical formula (20).
70. the method for the compound of preparation chemical formula (25),
Figure A2005800035220034C6
Comprise the compound that makes chemical formula (20)
Figure A2005800035220035C1
Compound with chemical formula (23)
Figure A2005800035220035C2
Reaction is to generate the compound of chemical formula (24)
With
Make the compound of chemical formula (24) go protection, to generate the compound of chemical formula (25).
71. prepare the method for compound (7),
Figure A2005800035220035C4
Comprise the compound that makes chemical formula (15)
Figure A2005800035220036C1
Go protection, to generate the compound of chemical formula (5)
Figure A2005800035220036C2
With
The compound of chemical formula (5) is converted into compound (7).
72. prepare the method for compound (7),
Figure A2005800035220036C3
Comprise the compound that makes chemical formula (26)
Figure A2005800035220036C4
Go protection, to generate the compound of chemical formula (5)
Figure A2005800035220037C1
With
The compound of chemical formula (5) is converted into compound (7).
73. prepare the method for compound (7),
Figure A2005800035220037C2
Comprise the compound that makes chemical formula (14)
Figure A2005800035220037C3
Compound with Formula I X
Figure A2005800035220037C4
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate compound (15)
Figure A2005800035220038C1
With
The compound of chemical formula (15) is converted into compound (7).
74. prepare the method for compound (7),
Figure A2005800035220038C2
Comprise the compound that makes chemical formula (25)
Compound with Formula I X
Figure A2005800035220038C4
Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate compound (26)
Figure A2005800035220039C1
With
The compound of chemical formula (26) is converted into compound (7).
75. prepare the method for compound (7),
Figure A2005800035220039C2
Comprise the compound of removing chemical formula (22)
In the cumyl protecting group, to generate the compound of chemical formula (14)
Figure A2005800035220039C4
Make the compound of chemical formula (14) and the compound of Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate compound (15)
With
The compound of chemical formula (15) is converted into compound (7).
76. prepare the method for compound (7),
Figure A2005800035220040C3
Comprise the compound that makes chemical formula (24)
Go protection, to generate the compound of chemical formula (25)
Figure A2005800035220041C1
Make the compound of chemical formula (25) and the compound of Formula I X
Figure A2005800035220041C2
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate compound (26)
With
The compound of chemical formula (26) is converted into compound (7).
77. prepare the method for compound (7),
Figure A2005800035220041C4
Comprise the compound that makes chemical formula (20)
Figure A2005800035220042C1
Compound with chemical formula (21) Reaction is to generate chemistry
The compound of formula (22)
Figure A2005800035220042C3
Make the compound of chemical formula (22) go protection, so that the compound of chemical formula (14) to be provided
Figure A2005800035220042C4
Make the compound of chemical formula (14) and the compound of Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate the compound of chemical formula (15)
Figure A2005800035220043C1
With
The compound of chemical formula (15) is converted into compound (7).
78. prepare the method for compound (7),
Comprise the compound that makes chemical formula (20)
Figure A2005800035220043C3
Compound with chemical formula (23)
Figure A2005800035220043C4
Reaction is to generate the compound of chemical formula (24)
Figure A2005800035220044C1
Make compound (24) go protection, so that the compound of chemical formula (25) to be provided
Figure A2005800035220044C2
Make the compound of chemical formula (25) and the compound of Formula I X
Figure A2005800035220044C3
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate the compound of chemical formula (26)
With
The compound of chemical formula (26) is converted into compound (7).
79. prepare the method for compound (7),
Figure A2005800035220045C1
Comprise the compound that makes chemical formula (9)
Figure A2005800035220045C2
Compound with chemical formula (12)
Reaction is to generate the compound of chemical formula (14)
Figure A2005800035220045C4
Make the compound of chemical formula (14) and the compound of Formula I X
Figure A2005800035220045C5
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate the compound of chemical formula (15)
With
The compound of chemical formula (15) is converted into compound (7).
80. prepare the method for compound (7),
Figure A2005800035220046C2
Comprise the compound that makes chemical formula (9)
Figure A2005800035220046C3
Compound with chemical formula (28)
Figure A2005800035220046C4
Reaction is to generate the compound of chemical formula (25)
Figure A2005800035220047C1
Make the compound of chemical formula (25) and the compound of Formula I X
Reaction in the presence of non-nucleophilic base, wherein X is selected from Br, Cl or I, to generate the compound of chemical formula (26)
Figure A2005800035220047C3
With
The compound of chemical formula (26) is converted into compound (7).
81. the compound of chemical formula (35)
Figure A2005800035220047C4
Or its salt.
82. the compound of chemical formula (36)
Or its salt.
83. prepare the method for compound (7),
Figure A2005800035220048C2
Comprise the compound that makes chemical formula (20)
Figure A2005800035220048C3
Compound with chemical formula (35)
Figure A2005800035220048C4
Reaction is to generate the compound of chemical formula (36)
Make the compound of chemical formula (36) go protection, so that the compound of chemical formula (10) to be provided
Figure A2005800035220049C2
With
The compound of chemical formula (10) is converted into compound (7).
CN 200580003522 2004-01-30 2005-01-31 Methods for making 4-tetrazolyl-4-phenylpiperidine compounds Pending CN1914192A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US54083904P 2004-01-30 2004-01-30
US60/540,839 2004-01-30
US60/552,982 2004-03-11

Publications (1)

Publication Number Publication Date
CN1914192A true CN1914192A (en) 2007-02-14

Family

ID=37722568

Family Applications (1)

Application Number Title Priority Date Filing Date
CN 200580003522 Pending CN1914192A (en) 2004-01-30 2005-01-31 Methods for making 4-tetrazolyl-4-phenylpiperidine compounds

Country Status (1)

Country Link
CN (1) CN1914192A (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106045894A (en) * 2016-06-12 2016-10-26 天津医科大学 3(4)-Substituted alkoxyphenoxy hydrocarbon PPAR (peroxisome proliferator-activated receptor) agonist and application thereof
CN108358863A (en) * 2018-03-08 2018-08-03 湖北佰智昂生物化工有限公司 A kind of method that zinc lewis acid Surfactant-Catalyzed prepares 5 '-substituted tetrazole compounds

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106045894A (en) * 2016-06-12 2016-10-26 天津医科大学 3(4)-Substituted alkoxyphenoxy hydrocarbon PPAR (peroxisome proliferator-activated receptor) agonist and application thereof
CN108358863A (en) * 2018-03-08 2018-08-03 湖北佰智昂生物化工有限公司 A kind of method that zinc lewis acid Surfactant-Catalyzed prepares 5 '-substituted tetrazole compounds

Similar Documents

Publication Publication Date Title
CN1024547C (en) Process for preparing cyclic amine compound
CN1136189C (en) Substd heterocyclic compounds preparing method thereof and pharmaceutical composition contg. them
CN1056605C (en) Novel N-(3,4-dichlorophenyl-propyl)-piperidine derivatves as selective human NK3-receptor antagonists
CN1298715C (en) Non-imidazole compounds as histamine H3 antagonists
CN1458921A (en) Process for making N-aryl-anthranilic acid and their derivatives
CN1159949A (en) Use of peptide compounds and pharmaceutically acceptable salts thereof for manufacturing medicament for treating diseases
CN1088207A (en) Pyrimidine compound
CN1065264A (en) The stereoselectivity preparation method of the piperidines that replaces
CN1239952A (en) 6-phenylpyridyl-2-amine derivatives useful as NOS inhibitors
CN1617869A (en) 4-(piperidyl- and pyrrolidyl-alkyl-ureido) -quinolines as urotensin ii receptor antagonists
CN1050376A (en) Acyl-CoA: cholesterol acyltransferase inhibitor
CN1060837A (en) Benzimidazolinone derivatives
CN1738806A (en) Oxo-azabicyclic compounds
CN86108205A (en) New thiazolium compounds and preparation method thereof and their pharmaceutical composition
CN1092425A (en) Indole derivatives, its manufacture method and medicinal use thereof
CN1021733C (en) Process for preparation of indolylpiperidine compounds
CN1081438A (en) Imdazole derivatives and preparation method thereof and the application on therapeutics
CN1020104C (en) Process for preparing cephene device
CN85101425A (en) Have Si Baige Eyring allied compound of phenylene and preparation method thereof
CN1805947A (en) Synthesis of 2-hydroxy-n,n-dimethyl-3-[[2-[1(r)-(5-methyl-2-furanyl)propyl]amino]-3,4-dioxo-1-cyclobuten-1-l]aminobenzamide
CN1041932C (en) Tricyclic quinoxalinedione derivatives
CN1914192A (en) Methods for making 4-tetrazolyl-4-phenylpiperidine compounds
CN1607201A (en) Method for the stereoselective synthesis of cyclic amino acids
CN1708491A (en) N-benzodioxolyl, N-benzodioxanyl and N-benzodioxepinyl arylcarbonxamide derivatives, and pharmaceutical compositions comprising them
CN1042152A (en) Be used as the thieno-pyrans of the new replacement of hypotensive agent

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C12 Rejection of a patent application after its publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20070214