CN105358534A - Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof - Google Patents

Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof Download PDF

Info

Publication number
CN105358534A
CN105358534A CN201480035262.XA CN201480035262A CN105358534A CN 105358534 A CN105358534 A CN 105358534A CN 201480035262 A CN201480035262 A CN 201480035262A CN 105358534 A CN105358534 A CN 105358534A
Authority
CN
China
Prior art keywords
compound
formula
enantiomer
formula iii
pure
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
CN201480035262.XA
Other languages
Chinese (zh)
Inventor
G·斯塔夫伯
J·克吕佐
F·里希特
G·劳斯
I·加齐奇斯米洛维奇
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.)
Lek Pharmaceuticals dd
Original Assignee
Lek Pharmaceuticals dd
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 Lek Pharmaceuticals dd filed Critical Lek Pharmaceuticals dd
Publication of CN105358534A publication Critical patent/CN105358534A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/44—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers
    • C07C209/48—Preparation of compounds containing amino groups bound to a carbon skeleton by reduction of carboxylic acids or esters thereof in presence of ammonia or amines, or by reduction of nitriles, carboxylic acid amides, imines or imino-ethers by reduction of nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/54—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions
    • C07C209/58—Preparation of compounds containing amino groups bound to a carbon skeleton by rearrangement reactions from or via amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/28—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines
    • C07C217/40—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having one amino group and at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the carbon skeleton, e.g. ethers of polyhydroxy amines having at least two singly-bound oxygen atoms, with at least one being part of an etherified hydroxy group, bound to the same carbon atom of the carbon skeleton, e.g. amino-ketals, ortho esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention is directed to a simple and economical process for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine via novel intermediates and a highly selective asymmetric synthesis leading to enantiopure (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-benzo[d] azepine or its (S)-enantiomer, in order to avoid or overcome chemical optical resolution.

Description

The novel synthesis of 8-chloro-1-methyl-benzo [d] azepines, new intermediate and production method thereof
Background
Obesity affects the millions of people in the whole world consumingly, and the quantity of obese people increases significantly.Although lifestyle change, on the other hand, for successful treatment, need pharmacotherapy.As the response to this challenge, numerous research and development concentrate on the 5-HT of the illness being used for the treatment of this life threatening 2Creceptor stimulant.Chlorine Ka Selin is one of challenging compound with using of most.
Up to now, provide only the preparation of racemize chlorine Ka Selin, then chiral separation is carried out to this enantiomorph, and only obtain the compound of the expectation of low yield.Therefore, for research and development for the preparation of the easy of racemize 8-chloro-1-methyl-benzo [d] azepines or related compound and the acceptable method of industrialization and be preferred for preparing enantiomer-pure or enantiomer-pure 8-chloro-1-methyl-benzo [d] azepines or related compound, especially chlorine Ka Selin (the chloro-1-methyl-2 of (R)-8-substantially, 3,4,5-tetrahydrochysene-1H-benzo [d] azepines) the concern of Stereoselective method progressively increase.The synthesis step that also special concern is final, the effective ways wherein for the closed loop of final intermediate produce 8-chloro-1-methyl-benzo [d] azepines or related compound, especially chlorine Ka Selin.
The description of prior art
The first synthesis of chlorine Ka Selin of Smith & Smith report in the patent application WO03086306 (scheme 1).This synthetic method uses 2-(4-chloro-phenyl-) ethamine 19 and trifluoacetic anhydride to react to carry out, and has wherein been separated trifluoroacetamide intermediate 20.In next step, expensive iodine chloride is used to make aromatic ring iodate under the existence of carbonate as alkali activator.Then use allyl bromide 98 activating terephthalamide amine 21 under biphasic condition, then under the existence of palladium catalyst, carry out Heck cyclisation in molecule, form outer-methylene derivatives 23.Then use Pd/C hydrogenation exocyclic double bond, after carrying out deprotection reaction, obtain racemize chlorine Ka Selin 9.
The first synthetic method of scheme 1. racemize chlorine card look standing forest.
The people such as Burbaum have submitted patent application (WO05019179) subsequently, which describes three kinds of new synthesis paths (scheme 2).All these synthesis paths start by p-chlorobenzene derivative.
The first path by with identical 2-(4-chloro-phenyl-) ethamine 19 used in WO03086306, but further transforms and can carry out with easier and efficient manner.Then use chlorpromazine chloride acylated amino group intermediate, form amide precursor 25, under the existence of aluminum chloride as Louis's activator, make it activate.Finally, acid amides 26 is reduced into racemize chlorine Ka Selin 9.By using typical optical resolution to obtain optically-active chlorine Ka Selin 18 to tartaric racemic mixture.
The second path uses amide precursor 25, is directly reduced to secondary amine 27, then uses aluminum chloride to activate under the existence of 1,2-dichlorobenzene being known as toxicity, obtains racemize chlorine Ka Selin 9.
The third path, by 2-(4-chloro-phenyl-) ethanol 28, first uses and is known as expensive phosphorus tribromide bromination.Use excessive 1-amino-2-propyl alcohol that bromide 29 is changed into alcohol precursor 30.After this, with thionyl chloride substituted alcohols under the existence of the DMA of catalytic amount, obtain and the identical solid hydrochloride precursor 27 also obtained in the second path.Finally, by Friedel-Craft alkylation, at AlCl 3existence under chloride precursor is closed, obtain expect chlorine Ka Selin.
Scheme 2. is by Exemplary chemical optical resolution synthesis of chiral chlorine Ka Selin.
In the ensuing patent application WO07120517 of the people such as Weigl, describe as similar (identical) method in WO05019179.Can observe to describe and use SiO 2-H 2o mixture solves some improvement of the separation method of Friedel-Craft Er Shi cyclization (this reaction of quencher).
The method that the patent application WO08070111 (scheme 3) of the people such as Gharbaoui is contained is from the coupled reaction between 2-(4-chloro-phenyl-) acetic acid 31 from 1-amino-2-propyl alcohol under different coupling reagent (trifluorophenylboronic acid, phenyl-boron dihydroxide, EDC or toluenesulphonic acids/Propanal dimethyl acetal) exists.Then different reductive agent (borine in THF or DMS, sodium borohydride is used, under the existence of iodine) reduce the mixture of the acid amides 32 that obtains or itself and a small amount of dihydro-oxazole compound 33, obtain similar alcohol precursor 30, it has appeared in the patent application (WO05019179 and WO07120517) of above-mentioned citation.Similar described in the patent application of final step and above-mentioned citation.
Scheme 3. passes through the synthesis of 2-kharophen and dihydro-oxazole precursor.
The patent application WO09111004 of the people such as Carlos discloses the method (scheme 4) of similar with WO05019179 with WO07120517 (identical).Describe the PBr using HBr gas instead costliness 3new bromination process.On the other hand, also describe and ask to protect the impurity 34 (to exist lower than 10% in end product) because using bromide to make 1-amino-2-propyl alcohol di obtain.
Scheme 4. passes through bromine intermediate to the improvement of synthetic method.
The patent application WO10148207 (scheme 5) of the people such as Demattel discloses the method with similar (identical) in the patent application of above-mentioned citation (WO05019179, WO07120517 and WO09111004).Based on thionyl chloride instead of harmful with dangerous HBr gas or the PBr of costliness 3describe new chlorination method.
Scheme 5. is by the improvement of chloromethylated intermediate to synthetic method.
Object of the present invention
The object of the present invention is to provide a kind of newly easy and the method for economy, it is for by new Intermediate Preparation 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines or related compound.The present invention also aims to the new intermediate being provided for preparing 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines or related compound, especially chlorine Ka Selin.The present invention also aims to the method being provided for producing these new intermediates.
Specific purposes of the present invention are the method for asymmetric synthesis providing a kind of high selectivity, it produces the chloro-1-methyl-2 of (R)-8-of enantiomer-pure or enantiomer-pure substantially, 3,4,5-tetrahydrochysene-1H-benzo [d] azepines, especially chlorine Ka Selin or its (S)-enantiomorph, to avoid or to overcome the chemical optics fractionation of the poor efficiency used in all art methods.
Summary of the invention
In order to solve the one or more of above-mentioned purpose, the invention provides the new racemize synthesis path for the synthesis of 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines (compd A) or its salt, example as shown in scheme 6.The present invention also provides high selectivity asymmetric synthesis path first, it is for the synthesis of the chloro-1-methyl-2 of (R)-8-, 3,4,5-tetrahydrochysene-1H-benzo [d] azepines ((R)-A) or its salt, or the chloro-1-methyl-2 of (S)-8-, 3,4,5-tetrahydrochysene-1H-benzo [d] azepines ((S)-A) or its salt, example as shown in scheme 7.
The synthesis path of scheme 6. racemize 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines, the * in its Chinese style represents asymmetric C atom.
Synthesis path is simply, contributes to industrialized and the racemization of chiral intermediate can not be used to transform.In addition, synthesis path only needs reagent that is simple and that be purchased and catalyzer.
Scheme 7. is for the asymmetry path (or its corresponding (S)-enantiomorph, condition is from (S)-I) of optically-active (R)-8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines.
Except racemize synthesis strategy, the invention provides effectively and the possibility of the asymmetric method of high selectivity.More favourable compared with the poor efficiency that this and the racemic mixture of the final chlorine Ka Selin used in prior art carry out chemical optics fractionation.High selectivity asymmetric synthesis uses optically-active raw material, its be simple, reliably and cost suitably favourable.Therefore, in the molecule of chirality Already in early stage step (first synthesis step).Without the need to using special asymmetric method based on expensive and harmful transition metal chiral catalyst or specific enzymes to induce enantioselectivity.
By the synthesis path of example as shown in scheme 6 and 7, the present invention is carrying out final closed loop relative in the contraposition of Cl substituting group, and the chirality of the methyl substituents in the present invention is inclined to without racemization with compared with the final closed loop of prior art that position between Cl substituting group routine as shown in such scheme 1-3 is carried out.
Following clause outlines formation in more detail and solves separately or in a joint manner the aspect of the object of the invention and preferred feature or embodiment.
1. for the preparation of the method by the 8-of following formula A example chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines or its salt:
* in its Chinese style represents asymmetric C atom, and the method comprises the following step:
A () is by the compound of following formula I:
Change into cyclic sulfonamides compound (sulfamidate) compound of Formula Il:
R in its Chinese style II is amino protecting group, and it is preferably from-Boc (tertbutyloxycarbonyl) ,-Cbz (carbobenzoxy oxygen base) ,-Bz (benzoyl) ,-Bn (benzyl) ,-Ac (ethanoyl) or-CH 2cH (OR 2) 2(wherein R 2the alkyl with 1-6 carbon atom, preferable methyl or ethyl or two R 2c2-or C3-alkylidene chain can be bonded to together, form 5-or 6-ring);
B the converting compounds of formula II is become the compound of Formula Il I by ():
R wherein in formula III with define in above-mentioned formula II identical; With
C the converting compounds of formula III becomes by ()
(c-1) compound of Formula Il Ia:
X wherein in formula III a is suitable for the leaving group of intramolecular cyclization Friedel-Craft Er Shi alkylated reaction or can be converted to the group of this kind of leaving group aptly, and wherein X is preferably-OH, tosylate, methanesulfonates, triflate or is selected from the halogen of Cl, Br, I, and wherein X is most preferably Cl or Br;
Or
(c-2) compound of Formula Il Ib:
It is identical that X wherein in formula III b and the compound of above-mentioned formula III a define;
Or
(c-3) compound of Formula Il Ic or IIIe:
Wherein R 2with above-mentioned formula II define identical;
Wherein R* is amino protecting group;
Wherein being formed in following situation of compound of formula III c can be omitted: the R in the compound of above-mentioned formula II and III has been represented as-CH defined above 2cH (OR 2) 2;
With;
D the converting compounds of formula III a or formula III b or formula III c or formula III e is become the compound of above-mentioned formula A by (), carry out through the following steps:
(d-1) carry out intramolecular cyclization reaction, it is preferably intramolecular cyclization Friedel-Craft or photochemically-induced ring-closure reaction;
(d-2) if optionally and be applicable to, reduction reaction; With
(d-3) if optionally and be applicable to, deprotection reaction.
The compound that the present invention comprises for the synthesis of the new key intermediate II hereafter defined " (its Chinese style II " is equivalent to formula II defined above, wherein R=R " be expressed as-CH defined above 2cH (OR 2) 2), III ' (wherein formula III ' compound be equivalent to formula III, IIIa, IIIb, IIIc and IIId, IIIe, IVa, IVc, IVd and IVe one of novel method, they are particularly valuable and for being prepared the chloro-1-methyl-2 of 8-by simple raw material, 3,4,5-tetrahydrochysene-1H-benzo [d] azepines (compd A) or one of its salt or corresponding enantiomorph.By method of the present invention, the intermediate crucial for raw material synthesizes with high yield with 1-amino-2-propyl alcohol (formula I) and final compd A or one of its salt or corresponding enantiomorph.By using cheap and simple raw material, the present invention is conducive to shortening and economic rational method, and it is for the preparation of the above-mentioned key intermediate enumerated and final compd A or one of its salt or corresponding enantiomorph.
In addition, in the embodiment of being undertaken by midbody compound II, wherein R is expressed as above-mentioned-CH 2cH (OR 2) 2, provide the refining synthesis path for final compd A or its salt or corresponding enantiomorph, without the need to making radicals R deprotection before intermediate compound III c cyclisation.
2. the method for clause 1, wherein step (a) comprises the following step:
(a-1) converting compounds of formula I is become the compound of following formula V:
It is identical that R in its Chinese style V and above-mentioned formula II define;
With
(a-2) converting compounds of formula V is become the compound of above-mentioned formula II;
Wherein step (a-2) optionally comprises:
(a-2-1) converting compounds of formula V is become the compound of following formula VI:
It is identical that R in its Chinese style VI and above-mentioned formula V define; With
(a-2-2) compound of oxidation-type VI subsequently, obtains the compound of formula II, is not preferably separated midbody compound VI.
3. the method for clause 2, wherein makes the compound of the formula I in step (a-1) and is selected from following reagent react:
(i) chloroformic acid benzyl ester, (PhCH 2oCO) 2o or N α-(carbobenzoxy-(Cbz) oxygen base) succinimide, to introduce-Cbz;
(ii) two di-tert-butyl carbonate, to introduce-Boc;
(iii) Benzoyl chloride, to introduce-Bz;
(iv) benzyl chloride or bromotoluene, to introduce-Bn;
V () acetic anhydride or Acetyl Chloride 98Min., to introduce-Ac;
(vi) X 3cH 2cH (OR 2) 2or OHC-CH (OR 2) 2, wherein X 3tosylate, methanesulfonates, triflate or halogen, preferred Cl or Br, and R 2identical with above-mentioned defined, to introduce-CH defined above 2cH (OR 2) 2(wherein R 2identical with above-mentioned defined).
4. the method for clause 2 or 3, wherein step (a-2-2) comprises the compound by using oxidizing formula VI, and described oxygenant is selected from RuO 2, NaIO 4, H 2o 2, urea-H 2o 2, cumene H 2o 2, m-CPBA (m-chlorine peroxybenzoic acid), NaBO 3xH 2o, MnO 2and ozone, preferred NaIO 4and RuO 2.
5. the method for any one of clause 1-4, wherein makes the compound of the formula II in step (b) and the compound of following formula VII react:
M in its Chinese style VII is selected from Li, MgBr and MgCl, preferred MgCl; And wherein this reaction preferably by CuX (X=Cl, Br, I), ZnCl 2, FeCl 3, more preferably by CuI or CuCl catalysis, and wherein particularly preferably by CuI catalysis, M=MgCl.
6. the method for any one of clause 1-5, wherein step (c) also comprises:
For step (c-1):
(c-1-1) if R right and wrong-CH defined above 2cH (OR 2) 2group, then remove radicals R from the compound of formula III, obtain the compound of Formula Il Id:
With
(c-1-2) compound of formula III d is made to react with the compound represented by following formula VIII:
Wherein X 1be selected from OH, F, Cl and Br, preferred Cl, and X 2be selected from OH, Cl and Br, and preferred Cl or Br,
Obtain the compound of formula III a, if wherein-X 2=OH-then this hydroxyl can be converted to tosylate, methanesulfonates, triflate, one of Cl, Br or I further, is preferably converted to Cl or Br; If and/or condition is-X 1=OH-then this hydroxyl is activated, and forms amido linkage;
For step (c-2):
(c-2-1)-reactions steps (c-1-1) similar as follows and (c-1-2)-subsequently with the amido linkage of the compound of the reductive agent reduction-type IIIa be applicable to, described reductive agent is preferably from LiAlH 4, RED-Al, DIBAL-H, diboron hexahydride, BH 3-THF mixture or hydride, obtain the compound of formula III b;
Or
(c-2-2)-similar as follows removing step (c-1-1)-make the compound of formula III d react with the compound represented by following formula I X subsequently:
Wherein X 2with above-mentioned formula VIII define identical,
In one pot of reductive amination reaction, use applicable reductive agent to obtain the compound of formula III b, described reductive agent is preferably from H 2/ Pd/C/HCl, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride, condition is if X 2=OH, then this hydroxyl can be converted to tosylate, methanesulfonates, triflate, one of Cl, Br or I further, is preferably converted to Cl or Br;
For step (c-3):
(c-3-1) if the R in the compound of-above-mentioned formula III is not yet expressed as-CH defined above 2cH (OR 2) 2, then following removing step (c-1-1) similarly-make the subsequently compound of formula III d with by formula X defined above 3cH 2cH (OR 2) 2(wherein X 3preferred Cl or Br, and R 2preferable methyl or ethyl) or OHC-CH (OR 2) 2(wherein R 2preferable methyl or ethyl) represent compound reaction, obtain the compound of formula III c, or
(c-3-2) if the R in the compound of-above-mentioned formula III is not yet expressed as-CH defined above 2cH (OR 2) 2, then make the compound of formula III with by formula X defined above 3cH 2cH (OR 2) 2(wherein X 3preferred Cl or Br, and R 2preferable methyl or ethyl) or OHC-CH (OR 2) 2(wherein R 2preferable methyl or ethyl) represent compound reaction, obtain the compound of formula III e, wherein R* and R is identical.
(c-3-3) if the R in the compound of-above-mentioned formula III is not yet expressed as-CH defined above 2cH (OR 2) 2then amino with protecting group protection, the preferred trityl of methyl (Tr) that described protecting group preferably replaces from unsubstituted benzyl (Bn) or the preferred Alpha-Methyl replaced, p-nitro, p-methyl or the benzyl (PMB) of p-methoxy substitution, many phenyl, the unsubstituted or C that fluoridizes 1-C 4-alkane alkylsulfonyl, preferably methylsulfonyl (methylsulfonyl; or trifyl (trifyl Ms); Tf) or unsubstituted or para-orientation, preferred p-methyl (tosyl group, Ts) replace benzenesulfonyl, unsubstituted or replace C 1-C 6the preferred ethanoyl of-alkyloyl (Ac) or the preferred benzoyl of aryl carbonyl (Bz); obtain the compound of formula III e; wherein R* is expressed as described group, is preferably expressed as-Bn ,-PMB ,-Tr ,-Ms ,-Tf ,-Ts ,-Ac or-Bz.
7. the method for any one of clause 1-6, the intramolecular cyclization reaction wherein in step (d/d-1) carries out in the following manner:
I () in the presence of a lewis acid, it is selected from AlCl 3, FeCl 3, InCl 3, InBr 3, Bi (OTf) 3, BiCl 3, Sc (OTf) 3, TeCl 4, BF 3× OEt 2, preferred anhydrous AlCl 3; Or under the existence of acid, it is selected from HOTf, pTsOH, TFA, CH 3sO 3h, H 3pO 4/ P 2o 5, H 2sO 4/ AcOH mixture, dense H 2sO 4or Tripyrophosphoric acid (PPA), and preferred H 2sO 4or PPA, or
(ii)-and for the compound-optionally by photochemically-induced ring-closure reaction of formula III a and IIIb, obtain:
(d-1-1) if the compound of the compound-following formula I Va of-cyclisation formula III a:
(d-1-2) if the compound of the compound-Shi A of-cyclisation formula III b;
(d-1-3) if the compound of-cyclisation formula III c or IIIe, the compound of following formula I Vc, IVd or IVe or its mixture:
Wherein R 3h, methyl or ethyl, and R* with define in aforesaid clause c-3-2 or c-3-3 identical, and
Reduction in the step (d-2) wherein only needed for the compound of formula IVa, IVc, IVd and IVe is undertaken by using applicable reductive agent, and described reductive agent is preferably from BH 3mixture, H 2/ metal catalyst (preferred Rh, Ru, Pd), NaBH 4/ H 2sO 4, LiAlH 4, Et 3n/HCOOH, RED-Al, DIBAL-H, H 2/ Pd/C/HCl or Zn/HCl, and most preferably BH 3-THF mixture or hydride, correspondingly, it is for the compound of reduction-type IVa; And H 2/ Pd/C/HCl, H 2/ PtO or Zn/HCl, it is for the compound of reduction-type IVc; And H 2/ PtO, it is for the compound of reduction-type IVd or IVe, if obtain and optionally obtain the compound of formula A at the compound forming formula IVe after deprotection.
8. the method for any one of aforesaid clause 1-7, wherein
The method is carried out through the following steps:
(a-1) by the compound (wherein R is preferably-Boc) of the converting compounds accepted way of doing sth V of formula I;
(a-2-1) make the compound of formula V and thionyl chloride react and
(a-2-2) with rear oxidation (preferably by use NaIO 4and RuO 2) midbody compound of formula VI, obtain the compound of formula II;
B () carries out similar to the ring-opening reaction of CuI catalysis with clause 5, wherein preferred M=MgCl, obtains the compound of formula III;
(c-1) through the following steps by the compound (middle X=Cl, Br) of the converting compounds accepted way of doing sth IIIa of formula III:
(c-1-1) R is removed; With
(c-1-2) react with bromoacetyl chloride or chloroacetyl chloride, obtain the compound of formula III a, wherein X=Br or Cl;
(d-1-1) by friedel-Crafts reaction, use preferred anhydrous AlCl 3or by the compound of photochemically-induced ring-closure reaction cyclisation formula III a, obtain the compound of formula IVa;
(d-2) preferably BH is used 3the compound of-THF mixture or hydride reduction formula IVa, obtains the compound of formula A.
9. the method for any one of aforesaid clause 1-7, wherein the method is carried out through the following steps:
(a-1) by the compound (wherein R is preferably-Boc) of the converting compounds accepted way of doing sth V of formula I;
(a-2-1) make the compound of formula V and thionyl chloride react and
(a-2-2) with rear oxidation (preferably by use NaIO 4and RuO 2) midbody compound of formula VI, obtain the compound of formula II;
B () carries out the ring-opening reaction similar with clause 5, wherein preferably by CuI catalysis, M=MgCl, obtains the compound of formula III;
(c-2) through the following steps by the compound (wherein X=Cl, Br) of the converting compounds accepted way of doing sth IIIb of formula III:
(c-2-1) remove R and react with bromoacetyl chloride or chloroacetyl chloride, obtain the compound of formula III a, wherein X=Br or Cl with
(c-2-2) subsequently with the amido linkage of the compound of the reductive agent reduction-type IIIa be applicable to, described reductive agent is preferably from LiAlH 4, RED-Al, DIBAL-H, diboron hexahydride, BH 3-THF mixture or hydride, most preferably BH 3-THF mixture;
(d-1-2) by friedel-Crafts reaction, use preferred anhydrous AlCl 3or by the compound of photochemically-induced ring-closure reaction cyclisation formula III b, obtain the compound of formula A.
10. the method for any one of clause 1-7, wherein the method is carried out through the following steps:
(a-1) by the compound of the converting compounds accepted way of doing sth V of formula I, wherein R is-CH defined above 2cH (OR 2) 2, react to carry out with the compound being selected from bromo-1, the 1-glycol dimethyl ether of 2-, bromo-1, the 1-diethoxyethane of 2-, 2,2-dimethoxy acetaldehyde and 2,2-diethoxy acetaldehyde preferably by making the compound of formula I;
(a-2-1) make the compound of formula V and thionyl chloride react and
(a-2-2) with rear oxidation (preferably by use NaIO 4and RuO 2) midbody compound of formula VI, obtain the compound of formula II;
B () carries out the ring-opening reaction similar with clause 5, wherein preferably by CuI catalysis, obtain the compound of formula III c, wherein OR 2define as above-mentioned;
(d-1-3) by friedel-Crafts reaction, the preferably anhydrous AlCl of use 3, dense H 2sO 4or the compound of PPA cyclisation formula III c, obtain the compound of formula IVc;
(d-2) preferably H is used 2the compound of/Pd/C/HCl or Zn/HCl reduction-type IVc, obtains the compound of formula A.
The method of 11. any one of aforesaid clause 1-7, wherein the method is carried out through the following steps:
(a-1) by the compound (wherein R is preferably-Boc) of the converting compounds accepted way of doing sth V of formula I;
(a-2-1) make the compound of formula V and thionyl chloride react and
(a-2-2) with rear oxidation (preferably by use NaIO 4and RuO 2) midbody compound of formula VI, obtain the compound of formula II;
B () carries out the ring-opening reaction similar with clause 5, wherein preferably by CuI catalysis, M=MgCl, obtains the compound of formula III;
(c-3) by the compound of the converting compounds accepted way of doing sth IIIc of formula III, carry out through the following steps:
(c-3-1) remove R and with above-mentioned formula X 3cH 2cH (OR 2) 2compound (wherein X 3preferred Cl or Br, and R 2preferable methyl or ethyl) or OHC-CH (OR 2) 2(wherein R 2preferable methyl or ethyl) reaction;
(d-1-3) by friedel-Crafts reaction, the preferably anhydrous AlCl of use 3, dense H 2sO 4or the compound of PPA cyclisation formula III c, obtain the compound of formula IVc or IVd;
(d-2) preferably H is used 2the compound of/Pd/C/HCl or Zn/HCl reduction-type IVc and preferably use H 2the compound of/PtO reduction-type IVd, obtains the compound of formula A.
The method of 12. any one of clause 1-11, wherein the method is stereoselective syntheses, and the enantiomer-pure substantially of the compound of its production A or the R enantiomorph of enantiomer-pure or its salt, be expressed as following formula (R)-A or its salt:
Wherein said stereoselective syntheses is from the enantiomer-pure substantially of the compound of the formula I represented by following formula (R)-I or the R-enantiomorph of enantiomer-pure:
And wherein this synthesis is carried out with stereoselective manner by the enantiomer-pure substantially of compound of formula II that represented by following formula (R)-II or the R-enantiomorph of enantiomer-pure:
Substantially the enantiomer-pure of compound of the formula III wherein converting compounds of formula (the R)-II in step (b) being become to be represented by following formula (R)-III or the R-enantiomorph of enantiomer-pure:
And wherein in building-up process, substantially retain chirality, produce the enantiomer-pure substantially of following formula (R)-A or the chipal compounds of enantiomer-pure or its salt.
The method of 13. any one of clause 1-11, wherein the method is stereoselective syntheses, and the compound of its production A is S-enantiomorph or its salt of enantiomer-pure or enantiomer-pure substantially, is expressed as following formula (S)-A or its salt:
Wherein said stereoselective syntheses is from the enantiomer-pure substantially of the compound of the formula I represented by following formula (S)-I or the S-enantiomorph of enantiomer-pure:
And wherein this synthesis is carried out with stereoselective manner by the enantiomer-pure substantially of compound of formula II that represented by following formula (S)-II or the S-enantiomorph of enantiomer-pure:
Substantially the enantiomer-pure of compound of the formula III wherein converting compounds of formula (the S)-II in step (b) being become to be represented by following formula (S)-III or the S-enantiomorph of enantiomer-pure:
And wherein in building-up process, substantially retain chirality, produce the enantiomer-pure substantially of following formula (S)-A or the chipal compounds of enantiomer-pure or its salt.
The method of 14. clause 1-9 and 11 any one, it produces the enantiomer-pure substantially of compound of formula A or the R-enantiomorph of enantiomer-pure or its salt that are represented by following formula (R)-A or its salt:
Wherein the racemic compound of step (c) Chinese style IIId is transformed the enantiomer-pure substantially of compound or the R-enantiomorph of enantiomer-pure of an accepted way of doing sth (R)-IIId,
Remove relative enantiomorph by the extra step of the one or many crystallization making the salt of (R)-IIId with chiral organic acid to carry out;
And wherein in building-up process, substantially retain chirality, produce the enantiomer-pure substantially of following formula (R)-A or the chipal compounds of enantiomer-pure or its salt.
The method of 15. clause 1-9 and 11 any one, the enantiomer-pure substantially of the compound of its production A or enantiomer-pure S-enantiomorph or its salt, represented by following formula (S)-A or its salt:
Wherein the racemic compound of step (c) Chinese style IIId is transformed the enantiomer-pure substantially of compound or the S-enantiomorph of enantiomer-pure of an accepted way of doing sth (S)-IIId,
Remove relative enantiomorph by the extra step of the one or many crystallization making the salt of (S)-IIId with chiral organic acid to carry out;
And wherein in building-up process, substantially retain chirality, produce the enantiomer-pure substantially of following formula (S)-A or the chipal compounds of enantiomer-pure or its salt.
The method of 16. clauses 14, wherein said chiral organic acid is selected from (R)-(-)-2-phenylpropionic acid.
The method of 17. clauses 14, wherein said chiral organic acid is selected from L-(-)-PLA.
18. formula IIIs ' compound or its salt:
Wherein formula III ' in R ' be expressed as: (i) R defined above; it is amino protecting group, and it is preferably from-Boc (tertbutyloxycarbonyl) ,-Cbz (carbobenzoxy) ,-Bz (benzoyl) ,-Bn (benzyl) ,-Ac (ethanoyl) or-CH 2cH (OR 2) 2(wherein R 2there is the alkyl of 1-6 carbon atom, preferable methyl or ethyl or two R 2c2-or C3-alkylidene chain can be bonded to together, form 5-or 6-ring) or be expressed as (ii)-H ,-COCH 2x or-CH 2cH 2-X (wherein X defines and preferably-OH, tosylate, methanesulfonates, triflate or halogen as above-mentioned, preferred Cl, Br or I, and wherein X most preferably Cl or Br).
Formula III ' compound or its salt be useful new intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.
The compound of 19. clauses 18, is expressed as the compound (H in R=formula III defined above) of formula III d defined above.
The compound of 20. clauses 18, is expressed as the compound of formula III a defined above (preferably wherein X is expressed as Cl, Br or I, more preferably Cl or Br) or IIIb (preferably wherein X is expressed as Cl, Br or I, more preferably Cl or Br).
The compound of 21. clauses 18, is expressed as compound (the preferably wherein R of above-mentioned formula III c 2for methyl or ethyl).
The compound of 22. any one of clause 18-21, its be represented by following formula (R)-III ' formula III ' the enantiomer-pure substantially of compound or the R-enantiomorph of enantiomer-pure or its salt:
R ' wherein in compound (R)-III ' with define in any one of clause 14-17 identical.
The compound or its salt of formula (R)-III ' is the useful especially new intermediate for stereoselective syntheses chlorine Ka Selin (compound (R)-A) or relevant (R)-8-chloro-1-methyl-benzo [d] azepine derivative or its salt.
The compound of 23. any one of clause 18-21, its be represented by following formula (S)-III ' formula III ' the enantiomer-pure substantially of compound or the S-enantiomorph of enantiomer-pure or its salt:
R ' wherein in compound (S)-III ' with define in any one of clause 18-21 identical.
The compound or its salt of formula (S)-III ' is the useful especially new intermediate for stereoselective syntheses (S)-chlorine Ka Selin (compound (S)-A) or relevant (S)-8-chloro-1-methyl-benzo [d] azepine derivative or its salt.
The compound of 24. clauses 22, is represented by the compound of above-mentioned formula (R)-IIId, is the salt form with chiral organic acid.
a* is chiral anion
The compound of 25. formulas (R)-(-)-2-phenylpropionic acid (R)-2-(3-chloro-phenyl-) third-1-ammonium.
The compound of 26. formulas (L)-(-)-phenyl-lactic acid (R)-2-(3-chloro-phenyl-) third-1-ammonium.
The compound of 27. clauses 23, is represented by the compound of above-mentioned formula (S)-IIId, is the salt form with chiral organic acid.
a* is chiral anion
The compound of 28. any one of clause 22-27 is preparing the purposes in diet pill, and described diet pill have 8-chloro-1-methyl-benzo [d] azepines skeleton, preferred chlorine Ka Selin or its salt.
29. for the production of the method for the compound of any one of clause 22-27, wherein the method comprise as any one of clause 1,5,8,9,12 or 13 the reactions steps (b) that defines, the method optionally also comprise as any one of clause 1,6,8,9,11,12 or 13 define reactions steps (c), (c-1), (c-2), (c-3), (c-1-1), (c-1-2), (c-2-1), (c-2-2) and (c-3-1) one or more.
The compound that 30. formula IVa represent:
It can be racemic, enantiomer-pure or enantiomer-pure substantially R-or S-type.
The compound of formula IVa is the useful new intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.
The compound of 31. clauses 30, it is the R-type (formula (R)-IVa) of enantiomer-pure or preferred enantiomer-pure substantially.
The compound of formula (R)-IVa is the useful especially new intermediate for stereoselective syntheses chlorine Ka Selin (compound (R)-A) or relevant (R)-8-chloro-1-methyl-benzo [d] azepine derivative or its salt.
32. for the production of the method for the compound of clause 30 or 31, wherein the method comprise as any one of clause 1,7,8,12 or 13 the reactions steps (d-1) that defines and/or (d-1-1), the method preferably uses anhydrous AlCl 3or h ν.
The compound or its salt that 33. formula IVc represent:
It can be racemic, enantiomer-pure or enantiomer-pure substantially R-or S-type, wherein R 2define and preferable methyl or ethyl as above-mentioned.
The compound of formula IVc is the useful new intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.
The compound of 34. clauses 33, it is the R-type (formula (R)-IVc) of enantiomer-pure or preferred enantiomer-pure substantially.
The compound of formula (R)-IVc is the useful especially new intermediate for stereoselective syntheses chlorine Ka Selin (compound (R)-A) or relevant (R)-8-chloro-1-methyl-benzo [d] azepine derivative or its salt.
The compound or its salt that 35. formula IVd represent:
It can be racemic, enantiomer-pure or enantiomer-pure substantially R-or S-type.
The compound of formula IVd is the useful new intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.
The compound of 36. clauses 35, it is the R-type (formula (R)-IVd) of enantiomer-pure or preferred enantiomer-pure substantially.
The compound of formula (R)-IVd is the useful especially new intermediate for stereoselective syntheses chlorine Ka Selin (compound (R)-A) or relevant (R)-8-chloro-1-methyl-benzo [d] azepine derivative or its salt.
The compound or its salt that 37. formula IVe represent:
It can be racemic, enantiomer-pure or enantiomer-pure substantially R-or S-type, wherein R* with define in c-3-2 or c-3-3 of clause 7 identical, preferred ptoluene-sulfonyl.
The compound of formula IVe is the useful new intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.
The compound of 38. clauses 37, it is the R-type (formula (R)-IVe) of enantiomer-pure or enantiomer-pure substantially.
The compound of formula (R)-IVe is the useful especially new intermediate for stereoselective syntheses chlorine Ka Selin (compound (R)-A) or relevant (R)-8-chloro-1-methyl-benzo [d] azepine derivative or its salt.
The compound or its salt that 39. formula X represent:
It can be racemic, enantiomer-pure or enantiomer-pure substantially R-or S-type, wherein R *define as above-mentioned and preferred ptoluene-sulfonyl.
The compound of formula X is the useful new intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.
The compound of 40. clauses 41, it is the R-type (formula (R)-X) of enantiomer-pure or enantiomer-pure substantially.
The compound of formula (R)-X is the useful especially new intermediate for stereoselective syntheses chlorine Ka Selin (compound (R)-A) or relevant (R)-8-chloro-1-methyl-benzo [d] azepine derivative or its salt.
41. for the production of the method for the compound of any one of clause 33-40, wherein the method comprise as any one of clause 1,7,10,11,12 or 13 the reactions steps (d-1) that defines and/or (d-1-3), the method preferably uses anhydrous AlCl 3, dense H 2sO 4or PPA.
42. formula II " compound represented:
R in its Chinese style II ' " is expressed as-CH defined above 2cH (OR 2) 2(wherein R 2methyl or ethyl or two R 2c2-or C3-alkylidene chain can be bonded to together, form 5-or 6-ring), it can be racemic, enantiomer-pure or enantiomer-pure substantially R-or S-type.
Formula II " compound be useful new intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.
The compound of 43. clauses 42, it is R-type (formula (the R)-II ") of enantiomer-pure or preferred enantiomer-pure substantially.
The compound of formula (R)-II ' is the useful especially new intermediate for stereoselective syntheses chlorine Ka Selin (compound (R)-A) or relevant (R)-8-chloro-1-methyl-benzo [d] azepine derivative or its salt.
44. for the production of the method for the compound of clause 42 or 43, wherein the method comprise as clause 1,2,3 (vi), 4,10,12 or 13 any one the reactions steps (a) that defines and/or (a-1) and/or (a-2) and/or (a-2-1) and/or (a-2-2).
The compound of 45. any one of clause 30-43 is preparing the purposes in diet pill, and described diet pill have 8-chloro-1-methyl-benzo [d] azepines skeleton, is preferably chlorine Ka Selin or its salt.
Detailed Description Of The Invention
Describe in further detail the present invention hereafter by with reference to preferred with embodiment favourable in addition and embodiment, these embodiments and embodiment should not be understood to limit.
The invention provides that be suitable for for the preparation of thrombotonin Antagonism 8-chloro-1-methyl-benzo [d] azepines or related compound or its salt, the particularly industrialization of chlorine Ka Selin, economical with easy asymmetric method and the key intermediate for its synthesis.Chlorine Ka Selin is selectivity 5-HT 2Creceptor stimulant, and the vitro test of this medicine is shown for 5-HT 2Cselectivity exceed other associated target.5-HT in presumption hypothalamus 2Cthe activation of acceptor activates POMC (POMC) and produces, and promotes to lose weight by satiety subsequently.For 8-chloro-1-methyl-benzo [d] azepines and related compound or its salt, particularly chlorine Ka Selin, synthesis path as herein described have benefited from simple reaction, appropriateness reaction conditions and be easy to that obtain with cheap chemical.Raw material for totally synthesizing is easy to obtain and is expressed as the amino propan-2-ol (I, (R)-I or (S)-I) of racemic, enantiomer-pure or enantiomer-pure substantially 1-.If the amino propan-2-ol ((R)-I) of (2R)-1-of the method basically enantiomer-pure or enantiomer-pure starts, then this synthesis produces the chlorine Ka Selin (formula (R)-A) of enantiomer-pure or enantiomer-pure substantially in the asymmetric mode of high selectivity.
Term used herein " substantially enantiomer-pure " refers to the enantiomeric excess (ee) of 70%ee or more, preferably 80%ee or more, more preferably 90%ee or more, most preferably 97%ee or more.
Term used herein " salt " refers to the salt form be applicable to arbitrarily of respective compound.Preferably, this salt is pharmaceutically acceptable.
The detailed overview of synthesis path provides hereinafter.
In a first step; can by amino for racemic, enantiomer-pure or enantiomer-pure substantially 1-propan-2-ol (I; (R)-I or (S)-I) in step (a-1), change into the compound of formula V, the R in its Chinese style V is amino protecting group or-CH 2cH (OR 2) 2(wherein R 2the alkyl with 1-6 carbon atom, preferable methyl or ethyl, or two R 2c2-or C3-alkylidene chain can be bonded to together, form 5-or 6-ring).
Term used herein " amino protecting group " refers to the group preventing the amine of the inventive method from transforming especially, and can be selected from known to " Greene ' sProtectiveGroupsinOrganicSynthesis ", 4th edition (PeterG.M.Wuts, TheodoraW.Greene; ISBN:978-0-471-69754-1) " amino protecting group " described in.Preferably, " amino protecting group " in the present invention is selected from-Boc (tertbutyloxycarbonyl) ,-Cbz (carbobenzoxy) ,-Bz (benzoyl) ,-Bn (benzyl) ,-Ac (ethanoyl).Particularly preferably use-Boc group.Can be found in " Greene ' sProtectiveGroupsinOrganicSynthesis " of above-mentioned reference by the specified conditions of these radical protection amino.Preferably, the present invention uses:
(i) chloroformic acid benzyl ester, (PhCH 2oCO) 2o or N α-(carbobenzoxy-(Cbz) oxygen base) succinimide, for introducing-Cbz;
(ii) two di-tert-butyl carbonate, for introducing-Boc;
(iii) Benzoyl chloride, for introducing-Bz;
(iv) benzyl chloride or bromotoluene, for introducing-Bn;
V () acetic anhydride or Acetyl Chloride 98Min., for introducing-Ac.
The scheme for-Boc protection particularly preferably as described in the people such as Hebeisen (TetrahedronLett.2011,52,5229).
In another embodiment, select to be used for the protecting group of the compound of the compound cyclisation accepted way of doing sth IV of formula III, wherein except such as above-mentioned disclosed group, can also use some other groups, it is comparatively not suitable for the cyclic sulfonamides forming formula II.This kind of preferably other " amino protecting group " is introduced by using following condition:
(vi) trityl chloride, for introducing-Tr;
(vii) p-toluenesulfonyl chloride, for introducing-Ts.
If above-mentioned group-CH 2cH (OR 2) 2as the radicals R in alternative, then the aspect that synthesis path is useful is, without the need to the amino deprotection in synthesis path subsequently as above, namely to remove radicals R.Preferably, the present invention uses (vi) by X defined above 3cH 2cH (OR 2) 2compound (the wherein X represented 3tolylsulfonyl ester, methanesulfonates, triflate or halogen, preferred Cl or Br, and R 2identical with above-mentioned defined, preferable methyl or ethyl) or OHC-CH (OR defined above 2) 2, wherein X 3tolylsulfonyl ester, methanesulfonates, triflate or halogen, preferred Cl or Br, and R 2with as above-mentioned define identical, for introducing-CH defined above 2cH (OR 2) 2(wherein R 2with as above-mentioned define identical).
Owing to being easy to the reactivity be applicable in utilizability, low cost and synthesis subsequently, so preferably bromo-1, the 1-glycol dimethyl ether of 2-, bromo-1, the 1-diethoxyethane of 2-, one of 2,2-dimethoxy acetaldehyde and 2,2-diethoxy acetaldehyde, for introducing group-CH 2cH (OR 2) 2.If one of 2,2-dimethoxy acetaldehyde and 2,2-diethoxy acetaldehyde are for reductive amination reaction, then the present invention utilizes the one pot reaction using the reductive agent be applicable to, the preferred H of described applicable reductive agent 2/ Pd/C/HCl, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride, most preferably H 2/ Pd/C/HCl.
After completing steps (a-1), obtain the compound of above-mentioned formula V, this synthesis path can use step (a-2) to carry out.This step (a-2) can be carried out according to single stage method or two-step approach.
In single stage method, can pass through as the people such as Melendez (Tetrahedron, the 59th volume; 15th phase; 2581-2616 page) scheme summarized, by utilizing SULPHURYL CHLORIDE or preferably 1,1 '-alkylsulfonyl diimidazole directly forms the compound of formula II by the compound of formula V.
In two-step approach, can by formed the midbody compound of formula VI step (a-2-1), oxidation, by the compound of the compound formation formula II of formula V, obtains the compound of formula II in the step (a-2-2) subsequently.Notably, without the need to the midbody compound of separate type VI, but at once can be oxidized after simple liquid extraction scheme, such as, by aqueous phase washing organic reaction phase, for except desalting.The midbody compound forming formula VI in step (a-2-1) is preferably by use thionyl chloride, such as by the people such as Melendez (Tetrahedron, 59th volume, 15th phase, 2581-2616 page) people (TetrahedronLett.2011 such as summary or Hebeisen, 52,5229) carry out under the condition described in.Subsequently can by the midbody compound of the formula VI in currently known methods oxidation step (a-2-2), such as by the people such as Melendez (Tetrahedron, 59th volume, 15th phase, 2581-2616 page) people (TetrahedronLett.2011 such as summary or Hebeisen, 52,5229) those methods described in.The oxygenant be applicable to can be selected from RuO 2, NaIO 4, H 2o 2, urea-H 2o 2, cumene H 2o 2, m-CPBA (m-chlorine peroxybenzoic acid), NaBO 3.xH 2o, MnO 2with ozone (Potassium Persulphate), its can with catalyzer coupling.Most preferably, the present invention uses NaIO 4with ruthenium catalyst (such as RuO 2or RuCl 3) catalysis.
Notably, formula II " compound represented:
Its Chinese style II " in R " is-CH defined above 2cH (OR 2) 2, represent the new and applicable intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.It is racemic or R-or the S-type of enantiomer-pure and even enantiomer-pure substantially that this compound has, preferred R-type.Compatibly according to as aforesaid clause 1,2,3 (vi), 4,10, any one of 12 or 13 the above-mentioned reactions steps (a) that defines and/or (a-1) and/or (a-2) and/or (a-2-1) and/or (a-2-2) produce this new intermediate.
After completing steps (a-2), obtain the compound of formula II, this synthesis path uses step (b) to carry out, to obtain the compound of formula III.The compound of formula II can in the organometallic compound open loop of use formula VII in step (b):
M in its Chinese style VII is the metal be applicable to for described open loop, and it is preferably from Li, MgBr and MgCl, most preferably MgCl.This reaction preferably uses CuX (X=Cl, Br, I), ZnCl 2, FeCl 3, more preferably use CuI or CuCl catalysis.Particularly preferably use CuI catalysis, M=MgCl.The reaction conditions be applicable to is by described in the people (TetrahedronLett.2011,52,5229) such as the people such as Melendez (Tetrahedron, the 59th volume, the 15th phase, 2581-2616 page) summary or Hebeisen.Most preferably, the present invention utilizes the Knochel type halogen metal of the iodo-benzene of the chloro-3-of 1-and chlorination sec.-propyl-magnesium to exchange, preferably when adding catalyzer copper (I) salt such as CuI.
Obviously, the ring-opening reaction in step (b) uses up-side-down configuration to carry out (see such scheme 7).Therefore, this synthesis, in the asymmetric mode of high selectivity, by suitably selecting the enantiomer-pure substantially of example as shown in aforesaid clause 12 and 13 and even the raw material I of enantiomer-pure to carry out, distinguishes production (R)-A or the enantiomer-pure substantially of (S)-A and even the end product of enantiomer-pure or its salt subsequently.Preferably this synthesis is the compound that raw material produces formula (the R)-A of enantiomer-pure and even enantiomer-pure substantially by the use enantiomer-pure substantially of formula (R)-I and even the compound of enantiomer-pure in the present invention.
Notably, the compound or its salt of formula III ' expression:
Wherein formula III ' in R ' be expressed as
(i) R defined above; it is amino protecting group, preferably from-Boc (tertbutyloxycarbonyl) ,-Cbz (carbobenzoxy) ,-Bz (benzoyl) ,-Bn (benzyl) ,-Ac (ethanoyl) or-CH 2cH (OR 2) 2(wherein R 2the alkyl with 1-6 carbon atom, preferable methyl or ethyl, or two R 2c2-or C3-alkylidene chain can be bonded to together, form 5-or 6-ring) or be expressed as
(ii)-H ,-COCH 2x or-CH 2cH 2(wherein X defines as above-mentioned-X, and preferred-OH, tolylsulfonyl ester, methanesulfonates, triflate or halogen, preferred Cl, Br or I, and wherein X most preferably Cl or Br), its representative is for the synthesis of the new of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt and the intermediate that is applicable to.This compound can be racemic or enantiomer-pure and even enantiomer-pure R-or S-type substantially, preferred R-type.This new intermediate be preferably expressed as one of aforesaid clause 15-19 the compound that defines.
If formula III ' compound be expressed as formula III a defined above, then residue X is most preferably expressed as Cl or Br.
If formula III ' compound be expressed as formula III b defined above, then residue X is most preferably expressed as Cl or Br.
If formula III ' compound be expressed as formula III c defined above, then residue R 2most preferably be expressed as methyl or ethyl.
In addition, this midbody compound compatibly according to as any one of aforesaid clause 1,5,8,9,12 or 13 define reactions steps (b) production.The method optionally also comprise as any one of aforesaid clause 1,6,8,9,11,12 or 13 define reactions steps (c), (c-1), (c-2), (c-3), (c-1-1), (c-1-2), (c-2-1), (c-2-2) and (c-3-1) one or more.
After step (b) completes, obtain the compound of formula III, this synthesis path can use step (c) to carry out.This step (c) can be divided into 3 optional steps, is provided respectively by above-mentioned steps (c-1), (c-2) and (c-3).
The first optional (c-1)
In first optional step (c-1), the compound by the converting compounds accepted way of doing sth IIIa of formula III:
X wherein in formula III a is suitable for the leaving group of intramolecular cyclization Friedel-Craft Er Shi alkylation reaction or suitably can be converted to the group of this kind of leaving group, and wherein X is preferably-OH, tosylate, methanesulfonates, triflate or halogen, preferably from Cl, Br, I, more preferably Cl or Br, most preferably X is expressed as Cl or Br.
The term used in the present invention " be suitable for the leaving group of intramolecular cyclization Friedel-Craft Er Shi alkylation reaction " and " suitably can be converted to the group of this kind of leaving group " refer at Lewis acid or formed in friedel-Crafts reaction or by photochemical reaction when acid exists and be suitable for the group of the electrophilic kind of reacting with aromatic substance." suitably can be converted to the group of this kind of leaving group " and have the ability of the leaving group changing into expectation routinely, this conversion is preferably carried out in position.The corresponding leaving group of its precursor group can by protecting with known protecting group of commonly using.The corresponding meaning of these terms becomes apparent further herein from the more specifically definition provided the open part of preferred embodiment.
If R right and wrong-CH defined above 2cH (OR 2) 2group, then step (c-1) can also protect the step (c-1-1) removing radicals R from the compound of formula III, obtains the compound of formula III d:
Notably, if the R in the compound of formula III is expressed as-CH defined above 2cH (OR 2) 2, then the compound that this compounds has been expressed as above-mentioned formula III c (is equivalent to above-mentioned formula III, wherein R=-CH 2cH (OR 2) 2), and the synthesis can being undertaken subsequently by optional (c-3), without the need to deprotection.
The specified conditions of the deprotection for radicals R are not particularly limited.Can, based on the summary condition of " Greene ' sProtectiveGroupsinOrganicSynthesis " of above-mentioned reference, select some and applicable condition to remove corresponding amino protecting group within the scope of the disposal of those skilled in the art.
After step (c-1-1) completes, step (c-1) can also comprise the step (c-1-2) that the compound of formula III d and the above-mentioned compound being expressed as formula VIII are reacted:
Wherein X 1be selected from OH, F, Cl and Br, preferred Cl, and X 2be selected from OH, Cl and Br, and preferred Cl or Br, obtain the compound of above-mentioned formula III a, if wherein-X 2this hydroxyl of=OH-can be converted to tosylate, methanesulfonates, triflate, one of Cl, Br or I further, preferred Cl or Br; If and/or condition is-X 1=OH-then this hydroxyl is activated, and forms amido linkage.Alcoholic extract hydroxyl group (i.e. X 2=OH) change into the halogen that is selected from Cl or Br or change into one of tosylate, methanesulfonates, triflate and can be undertaken by ordinary method, described ordinary method can be expressed as the method described in prior art document of above-mentioned reference.From the viewpoint of yield increasing friedel-Crafts reaction subsequently, preferably this conversion.But, can also make the alcoholic extract hydroxyl group in friedel-Crafts reaction and the excessive Lewis acid such as to use or acid-respons.If needed, then activate free acid (X 1=OH), form amido linkage, directly carry out acid amides synthesis subsequently.
Due to the reactivity of utilizability, low cost and friedel-Crafts reaction appropriateness subsequently, so the compound that preferred formula VIII represents is the compound being selected from chloroacetyl chloride or bromoacetyl chloride.
After step (c-1) completes, if according to above-mentioned asymmetric scheme, then in the step (d) of aforesaid clause 1, transform the compound of the first optional formula III a, obtain compound or its salt or itself R-or S-enantiomorph of formula A.
Respectively step (d) can be divided into first step (d-1) defined above and (d-1-1) and second step defined above (d-2).
Respectively in first step (d-1) and (d-1-1), in Friedel-Craft Er Shi alkylated reaction or photochemically-induced ring-closure reaction, transform the compound of formula III a, obtain the compound of formula IVa.This kind of Friedel-Craft Er Shi alkylated reaction can at Lewis acid or carry out under the existence of acid, described Lewis acid is selected from AlCl 3, FeCl 3, InCl 3, InBr 3, Bi (OTf) 3, BiCl 3, Sc (OTf) 3, TeCl 4, BF 3× OEt 2, preferred anhydrous AlCl 3, described in acid is selected from HOTf, pTsOH, TFA, CH 3sO 3h, H 3pO 4/ P 2o 5, H 2sO 4/ AcOH mixture, dense H 2sO 4or Tripyrophosphoric acid (PPA), preferred H 2sO 4or PPA.Most preferably Friedel-Craft Er Shi alkylated reaction utilizes anhydrous AlCl 3.Reaction conditions for transforming alcohols (i.e. X=OH) usually utilize excessive Lewis acid or acid, and the people such as MagnusRueping (BeilsteinJournalofOrganicChemistry2010, the 6,6th phase) review do not use excessive Lewis acid or the reaction conditions of acid.Or closed loop can be undertaken by photochemical reaction.This kind of photochemistry ring-closure reaction can be undertaken by using daylight or UV to be radiated in photochemical reactor.Photochemistry ring-closure reaction can use such as 100W light irradiation to be dissolved in the compound of the formula III a of applicable solvent such as the MeCN aqueous solution or the EtOH aqueous solution.Carry out in the immersion type reactor that the reactor body that photochemical reaction can preferably be made at the borosilicate glass immersing hole by the double wall borosilicate with insertion forms.Preferably, Hg-lamp (P=100-150W, λ=main > 300am) is pressed in can using.This Hg-lamp can be inserted the water-cooled immersion hole of double-walled arranged vertically.Reaction times is not particularly limited, can by such as mass spectroscopy monitoring reaction efficiency and selectivity.Usually, the reaction times of the friedel-Crafts reaction of 2-36 hour is enough, and the irradiation time of 0.25-4 hour can be enough.Conventional reaction conditions can be applied, and the condition of particularly preferably one of embodiment 15-18.
Subsequently, in step (d-2), with the compound of the reductive agent reduction-type IVa be applicable to, if according to above-mentioned asymmetric scheme, then can obtain compound or its salt or itself R-or S-enantiomorph of formula A.Described reductive agent is not particularly limited, but it is preferably from BH 3mixture, H 2/ metal catalyst (preferred Rh, Ru, Pd), NaBH 4/ H 2sO 4, LiAlH 4, Et 3n/HCOOH, RED-Al, DIBAL-H, and most preferably BH 3-THF mixture or hydride.Conventional reaction conditions can be applied, and the condition of particularly preferably embodiment 14.
Notably, the compound that represents of formula IVa:
Represent the new and applicable intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.This compound can be racemic or enantiomer-pure and even enantiomer-pure substantially R-or S-type, preferred R-type.
This compound compatibly according to as any one of clause 1,7,8,13 or 14 the above-mentioned reactions steps (d-1) that defines and/or (d-1-1) I produce, the method preferably uses anhydrous AlCl 3or h ν.
The second possibility (c-2)
In the step (c-2) of the second possibility, the compound by the converting compounds accepted way of doing sth IIIb of formula III:
It is identical that X wherein in formula III b and the compound of above-mentioned formula III a define.
Step (c-2) can be passed through above-mentioned steps (c-2-1) or be undertaken by above-mentioned steps (c-2-2) alternatively.
If according to the method for step (c-2-1), then can remove radicals R according to above-mentioned deprotection steps (c-1-1) from the compound of formula III, if R right and wrong-CH defined above 2cH (OR 2) 2group, then obtain the compound of Formula Il Id:
Notably, if the R in the compound of formula III is expressed as-CH defined above 2cH (OR 2) 2, then this compounds has been expressed as the compound of formula III c, and then by the synthesis that optional (c-3) carries out subsequently, without the need to deprotection.
After deprotection steps (c-1-1), first can according to the compound of above-mentioned reactions steps (c-1-2) by the converting compounds accepted way of doing sth IIIa of formula III d.After this, immediately by using the reductive agent be applicable to according to the compound of step (c-2-1) reduction-type IIIa, obtain the compound of formula III b, described applicable reductive agent is preferably from LiAlH 4, RED-Al, DIBAL-H, diboron hexahydride, BH 3-THF mixture or hydride, most preferably BH 3-THF mixture.
Or, if according to the method for step (c-2-2), then, maybe can by using the reductive amination reaction that be expressed as the compound of above-mentioned formula IX according to the compound of step (c-2-2) by the converting compounds accepted way of doing sth IIIb of formula III d:
Wherein X 2with above-mentioned formula VIII define identical, in the reaction of one pot of reductive amination, use applicable reductive agent to obtain the compound of formula III b, described applicable reductive agent is preferably from H 2/ Pd/C/HCl, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride, most preferably H 2/ Pd/C/HCl, condition is if X 2=OH, then this hydroxyl can be converted to tosylate, methanesulfonates, triflate, one of Cl, Br or I further, most preferably Cl or Br.The compound of formula IX can be bromoacetaldehyde (TheJournalofOrganicChemistry, 48, p.2111,1983), and is more preferably easy to the monochloroacetaldehyde that obtains.Conventional reaction conditions can be applied in reductive amination process.
By above-mentioned steps (c-2-1) or alternatively by after step (c-2-2) carries out step (c-2), the compound of the formula III b of second possibility is transformed in the step (d) of clause 1, if according to above-mentioned asymmetric scheme, then obtain compound or its salt or itself R-or S-enantiomorph of formula A.
This step (d) is equivalent to first step (d-1) defined above and (d-1-2) respectively.
Respectively in step (d-1) and (d-1-2), the compound of formula III b is transformed in Friedel-Craft Er Shi alkylated reaction or photochemically-induced ring-closure reaction, if according to above-mentioned asymmetric scheme, then obtain compound or its salt or itself R-or S-enantiomorph of formula A.Friedel-Craft Er Shi alkylated reaction or photochemically-induced ring-closure reaction can be carried out according to the described identical mode of step (d-1-1) in first possibility described in the compound to above-mentioned formula III a.
3rd possibility (c-3)
In the step (c-3) of the 3rd possibility, the compound by the converting compounds accepted way of doing sth IIIc of formula III:
Wherein R 2define as above-mentioned.The compound forming formula III c can be left in the basket in the case where there, and the R in the compound of above-mentioned formula II and III has been expressed as-CH defined above 2cH (OR 2) 2.
If the R in the compound of formula III has not been expressed as-CH defined above 2cH (OR 2) 2, then step (c-3) can be expressed as the above-mentioned steps (c-3-1) of aforesaid clause 6, if R right and wrong-CH defined above 2cH (OR 2) 2group, then comprise the above-mentioned deprotection steps step (c-1-1) for removing radicals R from the compound of formula III, obtain the compound of formula III d:
In addition, in reactions steps (c-3-1), make the compound of formula III d and be expressed as formula X defined above 3cH 2cH (OR 2) 2compound (wherein X 3preferred Cl or Br, and R 2preferable methyl or ethyl), most preferably bromoacetaldehyde dimethyl-acetal or bromoacetaldehyde diethyl acetal or be expressed as formula OHC-CH (OR defined above 2) 2compound (wherein R 2preferable methyl or ethyl) reaction, obtain the compound of formula III c.
After step (c-3-1), the compound of the formula III c in the 3rd possibility can be transformed in the step (d) of clause 1, if according to above-mentioned asymmetric scheme, then obtain compound or its salt or itself R-or S-enantiomorph of formula A.
This step (d) can be divided into first step (d-1) defined above and (d-1-3) and second step (d-2 defined above respectively.
Respectively in first step (d-1) and (d-1-3), in Friedel-Craft Er Shi alkylated reaction, with the compound to conversion type IIIc under the described substantially the same condition of step (d-1-1) in the compound to above-mentioned formula III a.Acetal (expression is adapted at the group that original position is converted to Friedel-Craft leaving group) in the compound of i.e. formula III c by Lewis acid or acid activation, the preferred anhydrous AlCl of described Lewis acid 3or BF 3× OEt 2, described in the preferred dense H of acid 2sO 4, PPA or MeSO 3h, so as when to form the compound of formula IVc ' and aromatic ring react, wherein R 2derived from the acetal group being not limited to methyl or ethyl.
But respectively in step (d-1) and (d-1-3), compound (the wherein R of formula III c defined above 2preferably from but be not limited to methyl or ethyl) in friedel-Crafts reaction by intramolecular cyclization, the difference according to reaction conditions obtains product.If friedel-Crafts reaction does not use solvent to carry out (net terms) in fusing mutually, be then obtained by reacting the compound of following formula I Vd, can separated salt acid salts between salt solution and methylene dichloride by being distributed in.Such as, if this reaction is carried out in a solvent, methylene dichloride, then can also be separated midbody compound and/or its hydrolysis derivative IVc of following formula I Vc ' under the condition identical with primary product ", wherein R 2define as above-mentioned, be preferably expressed as methyl or ethyl.In some cases, all three kinds of compounds are detected in the mixture.
In order to ensure more single method, the end product with double bond being obtained by reacting formula IVd should be forced.
This kind of Friedel-Craft Er Shi alkylated reaction applied in the present invention preferably carries out in the presence of a lewis acid, and described Lewis acid is preferably from AlCl 3, FeCl 3, InCl 3, InBr 3, Bi (OTf) 3, BiCl 3, Sc (OTf) 3, TeCl 4, most preferably from anhydrous AlCl 3.Friedel-Crafts reaction does not use solvent (net terms) or carries out in a solvent, and described solvent is selected from Nitromethane 99Min., arene, preferred oil of mirbane, chlorinated hydrocarbons, preferred methylene dichloride, and reaction continues 10min-36 hour.Friedel-Crafts reaction does not preferably use solvent (net terms) to carry out so that the compound of cyclisation formula IVd, and wherein secondary amine is not protected.
Contriver is surprisingly found out that, if the secondary amino group of the compound of formula III c is by amino protecting group (R*) protection, as being expressed as the structure of formula III e,
Then friedel-Crafts reaction solely produces the product with double bond, is expressed as the structure of formula IVe,
Wherein * defines chirality C-atom, and R* is expressed as protecting group.Amino protecting group R* used herein refers to the group of the secondary amine of the compound of protection IIIc, makes this group be applicable to step (d-1) respectively, and the friedel-Crafts reaction condition of application in (d-1-3).This kind of amino protecting group R* is only limitted to carry out under the reaction conditions of described reactions steps (d) because of its suitability, and can be selected from known to " Greene ' sProtectiveGroupsinOrganicSynthesis ", 4th edition (PeterG.M.Wuts, TheodoraW.Greene; ISBN:978-0-471-69754-1) " amino protecting group " quoted from.Preferably, be selected from unsubstituted benzyl (Bn) or the preferred Alpha-Methyl replaced for amino protecting group R* of the present invention, the preferred trityl of methyl (Tr) that p-nitro, p-methyl or the benzyl (PMB) of p-methoxy substitution, many phenyl replace, unsubstituted or fluoridize C 1-C 4preferred methylsulfonyl (the methylsulfonyl of-alkane alkylsulfonyl; or trifyl (trifyl Ms); Tf) or preferred p-methyl (tosyl group, Ts) that is unsubstituted or para-orientation replace benzenesulfonyl, unsubstituted or replace C 1-C 6the preferred ethanoyl of-alkyloyl (Ac) or the preferred benzoyl of aryl carbonyl (Bz); obtain the compound of formula III e; wherein R* is expressed as described group, is preferably expressed as-Bn ,-PMB ,-Tr ,-Ms ,-Tf ,-Ts ,-Ac or-Bz.
Protective reaction medium preferably from aprotic solvent, preferred methylene dichloride.
The method of the starting compound of preparation formula IIIe can be divided into two optional (c-3-2) and (c-3-3).In step (c-3-2), make the compound of formula III, wherein R right and wrong-CH defined above 2cH (OR 2) 2group, and be expressed as formula X defined above 3cH 2cH (OR 2) 2compound (wherein X 3preferred Cl or Br, and R 2preferable methyl or ethyl), most preferably bromoacetaldehyde dimethyl-acetal or bromoacetaldehyde diethyl acetal or be expressed as formula OHC-CH (OR defined above 2) 2compound (wherein R 2preferable methyl or ethyl) reaction, do not apply and remove in advance, obtain the compound of formula III e, wherein R* is limited to substituent R.
In step (c-3-3), by introducing the compound of reaction by the preparation of compounds of formula IIIe of formula III c of protecting group by such as following method:
The methyl that the benzyl of the preferred Alpha-Methyl of-unsubstituted benzyl or replacement, p-nitro, p-methyl or p-methoxy substitution or many phenyl replace, by with corresponding halid reaction, described halogenide is selected from muriate, bromide or iodide, in the basic conditions;
-the unsubstituted or C that fluoridizes 1-C 4-alkane alkylsulfonyl; preferred trifyl (trifyl; or preferred p-methyl (tosyl group that is unsubstituted or para-orientation Tf); Ts) benzenesulfonyl replaced; by reacting with corresponding sulfonic acid halide; the preferred muriate of described sulfonic acid halide, such as toluene sulfonyl chloride (TsCl) or alkylsulfonyl hydride, such as trifluoromethanesulfanhydride anhydride (Tf 2o), in the basic conditions; Or
-or C that is unsubstituted or that replace 1-C 6-alkyloyl, preferred ethanoyl or aryl carbonyl, preferred benzoyl, by reacting with corresponding carboxylic acid halides, the preferred acyl chlorides of described carboxylic acid halides or acetyl anhydride, such as acetic anhydride (Ac 2o) or Benzoyl chloride, in the basic conditions.
In rapid (c-3-3), some the protected groups can not introduced in the method for step (c-3-2) can be introduced.This kind of group is expressed as alkylsulfonyl protecting group, and in view of yield and purity, it is preferred in Friedel-Craft transforms.The medium of protective reaction preferably from aprotic solvent, most preferably from methylene dichloride.
If R is-CH 2-CH (OR 2) 2, then can by the compound of formula III c used in the compound producing step of the formula II of step (b) (c-3-3), if or R not right and wrong-CH defined above 2cH (OR 2) 2group, then can by the compound of the formula III c used in the compound producing step (c-3-3) of the formula III in step (c-3-1).
After Friedel-Craft transforms, usually separate type IVc ', IVc through the following steps ", the compound of IVd and IVe: make this reaction mixture quencher with water; neutralize this mixture with alkali such as sodium hydroxide, and with the solvent extraction product with water immiscibility, then except desolventizing.
Subsequently, in step (d-2), if according to above-mentioned asymmetric scheme, then with the reductive agent reduction-type IVc ', the IVc that are applicable to ", the compound of IVd or its mixture, obtain compound or its salt or itself R-or S-enantiomorph of formula A.Described reductive agent is not particularly limited, but preferably from H 2/ Pd/C/HCl or Zn/HCl.
Or, in step (d-2), use reductive agent by the compound of the compound of formula IVe reduction accepted way of doing sth X:
Described reductive agent preferably from hydroborate, such as alkali metal borohydride, preferred NaBH 4or borane complexes, preferred BH 3tHF, aluminum hydride, preferred LiAlH 4, DIBALH, RedAl, use NEt 3/ HCO 2h, Zn are in acid condition or by catalytic hydrogenation, use transition-metal catalyst, it preferably from palladium, platinum, nickel, ruthenium, most preferably uses catalytic hydrogenation, use transition-metal catalyst.Preferred method for the compound of reduction-type IVd or IVe is the catalytic hydrogenation using platinum oxide.
In step (d3); standard scheme well known by persons skilled in the art is used to make the amino protecting group R* deprotection of the compound of formula X; described standard scheme can be selected from acid or basic hydrolysis or hydrogenation, obtains end product or its salt of formula A, preferred chlorine Ka Selin or its salt.
Or, can by first removing protecting group, then carrying out finally reducing the end product of the converting compounds accepted way of doing sth A of formula IVe.But, due to the tautomeric possibility of enamine-imines about unprotected intermediate, so this synthesis path is that grade is lower in yield and purity.Due to same cause, so introduce amino protecting group R* by step (c-3-3) before the Friedel-Craft Er Shi alkylation of preferably application in step (d).
Notably, the compound or its salt of formula IVc ' is expressed as:
Represent the new and applicable intermediate for the synthesis of compd A or relevant 8-chloro-1-methyl-benzo [d] azepine derivative, preferably chlorine Ka Selin or its salt.This compound can be racemic or enantiomer-pure and even enantiomer-pure substantially R-or S-type, preferred R-type.
The above-mentioned reactions steps (d-1) compatibly defined according to any one of clause 1,7,10,11,12 or 13 and/or (d-1-3) produce this compound, and the method preferably uses anhydrous AlCl 3, dense H 2sO 4or PPA.
By above-mentioned synthesis, the present invention provides the possibility for raw material asymmetric synthesis 8-chloro-1-methyl-benzo [d] azepine derivative by using enantiomer-pure or enantiomer-pure substantially, preferably chlorine Ka Selin or its salt first time.In this manner, the invention provides appropriate, economical and optionally synthesize.In addition, the invention provides the experience about the new key intermediate for the synthesis of this compounds and the corresponding mode of production thereof.
Or, complete method of the present invention can be implemented by step (a)-(d) of clause 1, use racemize raw material and intermediate, and eventually through the enantiomorph with tartrate crystallization diastereomeric salt separating compound A, obtain pharmaceutically useful (the R)-isomer of chlorine Ka Selin, described in WO05019179, but because remove the relative enantiomorph do not utilized to eliminate the over half of material in final step, competitive power in this way can be regarded as challenging.
The another kind of enantiomorph selecting to be to be separated in the step of early stage intermediate.Such as, carrying out optical resolution with the EtOH solution of L MALIC ACID to non-chlorination analogue 2-phenyl-1-propylamine at 70 DEG C is disclosed in following patent application: WO008073789, WO01090057, WO01089530.Be surprisingly found out that, it is invalid for carrying out optical resolution with L MALIC ACID to chlorinated derivatives IIId in competitive power, and this precipitates malate owing to use racemize IIId.
Find by using the chiral organic acid be comparatively of little use to make diastereomeric salt crystallization successfully can be separated the compound of the formula III d of enantiomer-pure or enantiopure form substantially.
Therefore, by processing the racemic compound of separate type IIId in organic solvent with chiral organic acid, the alkanoic acid that preferably replaces from phenyl
From wherein precipitating a kind of enantiomorph, it is form that is highly enriched or enantiomer-pure substantially.Most preferred chiral acid is 2-phenylpropionic acid and PLA.Such as, by processing compound III d in ethanol with (R)-(-)-2-phenylpropionic acid (RPP), compound (the R)-IIId of transport disengaging height enriched form in a step, and by making the salt recrystallization of separation further, obtain the isomer of the enantiomer-pure substantially had more than 98%e.e..
By making the racemic compound crystallization of formula III d obtain similar result in toluene with L-(-)-PLA (LPL).
Enantiomeric purity can be improved further by one or many crystallization, obtain the material of enantiomer-pure.
By mixing two kinds of compositions and solvent, heating higher than 50 DEG C and carry out crystallization to dissolve whole or most of solid matter, optionally impurity screening and to cool this solution with crystal salt.By filtering or the material of centrifugal and dry precipitation separation.
By alkalization, such as, use the NaOH aqueous solution, then with evaporating the compound of formula (the R)-IIId obtained reclaiming alkali form with the immiscible solvent extraction of water.This compounds can be further used for step (c) and (d), obtains the compound of the formula A of enantiomer-pure or enantiopure form substantially, the chlorine Ka Selin of preferred (R) type or its salt.
(R)-(+)-2-phenylpropionic acid (SPP) or D-(+)-PLA (DPL) can be used to carry out similar conversion for (S)-enantiomorph.
Disclosed optional manner recently can be passed through passed through 2-(3-chloro-phenyl-) propionitrile by 2-(3-chloro-phenyl-) acetonitrile, be then reduced into the racemic compound of 2-(3-chloro-phenyl-) third-1-amine synthesis type IIId, the method is reported in J.Med.Chem.2013,56,4786-4797) and J.Am.Chem.Soc.2013, in 135,2100-2103 (scheme 8).
Scheme 8
Those skilled in the art can select this enantio-selectivity method, and it is at yield and be more favourable in price.Use the chiral amino propyl alcohol of the formula I of the following step (a)-(d) of the present invention or according to step (a), (b) and (c) or according to the racemic compound of scheme 8 preparation formula IIId, can be provided in the chance of not carrying out optical resolution in the final step of preparation of pharmaceutical compounds such as chlorine Ka Selin by the selection between the optical resolution of diastereomeric salt and other step (d) subsequently.If used by the method for p-chlorine replacement as the prior art of raw material, then the fractionation in final step is inevitable.
With can the detailed description of the embodiment of the present invention (embodiment) of the mode of current embodiment again.
Embodiment 1: by amino propan-2-ol (I) synthesizing tertiary butyl-2-(the hydroxypropyl)-carbamate (V-Boc) of 1-:
Raw material 1-amino-2-propyl alcohol (I is put in the flask installing magnetic stirring bar; 3.0g, 60mmol), be dissolved in dry methyl alcohol (MeOH) (110mL).Add alkali activator Et 3n (16mL), add lentamente subsequently two carbonic acid two-tert-butyl ester (60mmol, 13.1g), at 60 DEG C, the reaction mixture obtained is stirred 30 minutes in nitrogen atmosphere.After having reacted, reduction vaporization methyl alcohol, dilute with water residue, then uses ethyl acetate (30mL) to extract.By salt water washing organic phase, use anhydrous Na 2sO 4drying, reduction vaporization organic solvent.Obtain colorless oil as product (V-Boc, 6.8g, 97% yield), use 1h, 13cNMR and IR analysis and characterization.
1HNMR(500MHz，CDCl 3，ppm)δ5.20(bs，NH)，3.85(m，1H)，3.25(m，1H)，3.05(bs，OH)，2.90(m，1H)，1.43(s，9H)，1.10(d，J＝8Hz，3H)；
13CNMR(125MHz，CDCl 3，ppm)δ157.0，79.7，67.6，48.1，28.5，20.8；
IR (only): ν=3351 (broad peak, OH), 2975,2931,1684 (CO), 1514,1365,1248,1167cm -1.
Embodiment 2: by the amino propan-2-ol ((R)-I or (S)-I) of chirality 1-synthesize the optically-active tertiary butyl-2-(hydroxypropyl)-carbamate ((R)-V-Boc or (S)-V-Boc:
Raw material 1-amino-2-propyl alcohol ((R)-I or (S)-I is put in the flask installing magnetic stirring bar; 13mmol, 0.98g), be dissolved in dry MeOH (40mL).Add alkali activator Et 3n (4mL), add lentamente subsequently two carbonic acid two-tert-butyl ester (1 equivalent calculates according to raw material), at 60 DEG C, the reaction mixture obtained is stirred 30 minutes in nitrogen atmosphere.After having reacted, reduction vaporization methyl alcohol, dilute with water residue, then uses ethyl acetate (2x20mL) to extract.By the organic phase that salt water washing merges, use anhydrous Na 2sO 4drying, reduction vaporization organic solvent.Obtain colorless oil as product ((R)-V-Boc or (S)-V-Boc, 2.21g, 95% yield), analyze with HPLC, use 13cNMR spectrography confirms.
13CNMR(125MHz，CDCl 3，ppm)δ157.0，79.8，67.6，48.2，28.6，20.8。
Embodiment 3: by the tertiary butyl-2-(hydroxypropyl)-carbamate (V-Boc) synthesizing tertiary butyl-5-methyl isophthalic acid, 2,3-Evil thiazolidine-3-manthanoate-oxide compound (VI-Boc)
Put in the flask installing magnetic stirring bar and be dissolved in CH 2cl 2(40mL) imidazoles (4.10g, 60mmol), is cooled to 0 DEG C by this solution.After this, SOCl is added lentamente 2(1.3mL, 18mmol) is at CH 2cl 2in solution, by this reaction mixture 20 DEG C stir 1 hour, be cooled to-5 DEG C.Then by the tertiary butyl-2-(hydroxypropyl)-carbamate (V-Boc, 1.75g, 10mmol) at CH 2cl 2in solution instill this reaction mixture lentamente, at 20 DEG C of vigorous stirring 2-3 hour.First this reaction mixture is diluted with deionized water.Be separated organic phase, with aqueous citric acid solution (50mL) and salt solution (50mL) washing, then solvent evaporated under reduced pressure.Obtain solid matter (isomer mixture) (VI-Boc, 1.99g, 90% yield), use 13cNMR spectrography characterizes.
13CNMR(125MHz，CDCl 3，ppm)δ156.1，83.8，79.8，71.7，67.8，50.6，46.1，28.6，28.3，20.117.1。
Embodiment 4: by the tertiary butyl-2-(hydroxypropyl)-carbamate (V-Boc) directly synthesizing tertiary butyl-5-methyl isophthalic acid, 2,3-Evil thiazolidine-3-manthanoate-2,2-dioxide (II-Boc)
Put in the flask installing magnetic stirring bar and be dissolved in CH 2cl 2(40mL) imidazoles (60mmol), is cooled to 0 DEG C by this solution.After this, SOCl is added lentamente 2(18mmol) at CH 2cl 2in solution, by this reaction mixture 20 DEG C stir 1 hour, be cooled to-5 DEG C.Then by the tertiary butyl-2-(hydroxypropyl)-carbamate (V-Boc, 10mmol) at CH 2cl 2in solution instill this reaction system lentamente, 20 DEG C of vigorous stirring 2 hours.First this reaction mixture is diluted with deionized water.Be separated organic phase, with aqueous citric acid solution (50mL) and salt solution (50mL) washing.Then organic phase is used for further oxidising process, wherein at 0 DEG C by NaIO 4the aqueous solution (5.8g is in 50mL water) joins in this system lentamente, then adds RuO 2h 2o catalyzer (90mg).Then by this reaction system 0 DEG C of vigorous stirring 1 hour, then at room temperature vigorous stirring 2-3 hour.First dilute this reaction mixture with aqueous ascorbic acid, be separated organic phase, with salt solution (50mL) washing, solvent evaporated under reduced pressure.The thick material of vacuum-drying (pale yellow oil), obtains final crystallized product (II-Boc, 1.91g, 80% yield), uses 1h and 13cNMR spectrography characterizes.
1HNMR(500MHz，CDCl 3，ppm)δ4.95(m，1H)，4.06(m，1H)，3.62(m，1H)，1.60(d，J＝7.5Hz，3H)，1.51(s，9H)；
13CNMR(125MHz，CDCl 3，ppm)δ148.8，85.5，76.4，51.9，28.1，18.2；
IR (only): ν=1716,1332,1198,1144,763cm -1.
Embodiment 5: the optically-active tertiary butyl-5-methyl isophthalic acid, the direct synthesis of 2,3-Evil thiazolidine-3-manthanoate-2,2-dioxide ((R)-II-Boc or (S)-II-Boc)
Put in the flask installing magnetic stirring bar and be dissolved in CH 2cl 2(45mL) imidazoles (66mmol), is cooled to 0 DEG C by this solution.After this, SOCl is added lentamente 2(19.8mmol) at CH 2cl 2in solution, by this kind of reaction mixture 20 DEG C stir 1 hour, be cooled to-5 DEG C.By the tertiary butyl-2-(hydroxypropyl)-carbamate ((R)-V-Boc or (S)-V-Boc, 11mmol) at CH 2cl 2in solution instill this reaction system lentamente, 20 DEG C of strong stirrings 2 hours.First this reaction mixture is diluted with deionized water.Be separated organic phase, with aqueous citric acid solution (50mL) and salt solution (50mL) washing.Then organic phase is used for further oxidising process, wherein at 0 DEG C by NaIO 4the aqueous solution (6.0g is in 50mL water) joins in this system lentamente, then adds RuO 2h 2o catalyzer (110mg).Then at 0 DEG C by this reaction system vigorous stirring 1 hour, then stirring at room temperature 3 hours.First dilute this reaction mixture with aqueous citric acid solution, be separated organic phase, with salt solution (50mL) washing, then solvent evaporated under reduced pressure.The thick material of vacuum-drying (pale yellow oil), obtains yellow crystalline product ((R)-II-Boc or (S)-II-Boc, 2.32g, 86% yield).Analytical data and above-described embodiment 4 (HPLC analyze (single enantiomer) and 1h, 13cNMR spectrography) consistent.
Embodiment 6: by the tertiary butyl-5-methyl isophthalic acid, 2,3-Evil thiazolidine-3-manthanoate-2,2-dioxide (II-Boc) synthesizing tertiary butyl-(2-(3-chloro-phenyl-) propyl group) carbamate (III-Boc)
Put in the double-neck flask installing magnetic stirring bar and rubber plug and be dissolved in Et 2the iodo-benzene (1.42g, 6mmol) of the chloro-3-of 1-of O, is cooled to-14 DEG C.After this, iPrMgCl (3ml, 2M ethereal solution, 6mmol) is instilled lentamente reaction system (dripping for 1 hour), this reaction mixture is stirred 2.5 hours at 0 DEG C.Then add CuI (11mg), this reaction system is stirred 30 minutes again.Finally, add 5-methyl isophthalic acid lentamente immediately at-10 DEG C, 2,3-Evil thiazolidine-3-manthanoate-2,2-dioxide (II-Boc, 1.18g, 5mmol) is at Et 2suspension in O, by this kind of reaction system 0 DEG C of vigorous stirring 2 hours.First dilute this reaction mixture at room temperature aqueous citric acid solution, stir 1 hour, so that separation of phases well.Then use salt water washing organic phase, use Na 2sO 4drying, evaporating solvent.The thick oily matter of vacuum-drying, obtains colorless oil (III-Boc, 1.33g, 99% yield), uses 1h and 13cNMR and IR spectrography characterizes.
1HNMR(500MHz，CDCl 3，ppm)δ7.16-7.05(m，3H)，4.45(bs，NH)，3.32(m，1H)，3.15(m，1H)，2.87(m，1H)，1.30(s，9H)，1.22(d，J＝8Hz，3H)；
13CNMR(125MHz，CDCl 3，ppm)δ156.1，146.6，134.6，130.1，127.6，126.9，125.7，79.5，47.4，40.1，20.6，19.1；
IR (only): ν=3352 (br, NH), 2974,2930,1692,1506,1247,1163cm -1.
Embodiment 7: by the chirality tertiary butyl-5-methyl isophthalic acid, 2,3-Evil thiazolidine-3-manthanoate-2,2-dioxide ((R)-II-Boc or (S)-II-Boc) synthesizes the optically-active tertiary butyl-(2-(3-chloro-phenyl-) propyl group) carbamate ((R)-III-Boc or (S)-III-Boc)
Put in the double-neck flask installing magnetic stirring bar and rubber plug and be dissolved in Et 2the iodo-benzene (0.24g, 1mmol) of the chloro-3-of 1-of O, is cooled to-14 DEG C.After this, iPrMgCl is instilled reaction system (dripping for 1 hour) lentamente as 2M ethereal solution (1mmol), this reaction mixture is stirred 2.5 hours, effectively to carry out Grignard permutoid reaction at 0 DEG C.Then add CuI (5mg), this reaction system is stirred 30 minutes again.Finally, add 5-methyl isophthalic acid lentamente immediately at-10 DEG C, 2,3-Evil thiazolidine-3-manthanoate-2,2-dioxide ((R)-II-Boc or (S)-II-Boc, 0.85mmol) is at Et 2suspension in O, by this kind of reaction system at 0 DEG C of vigorous stirring overnight.First dilute this reaction mixture at room temperature aqueous citric acid solution, stir 1 hour, so that separation of phases well.Then use salt water washing organic phase, use Na 2sO 4drying, evaporating solvent.The thick oily matter of vacuum-drying, obtains colorless oil ((R)-III-Boc or (S)-III-Boc, 86% yield).Analytical data and above-described embodiment 6 (HPLC analyze (single enantiomer) and 1h, 13cNMR spectrography) consistent.
Embodiment 8: make the tertiary butyl-(2-(3-chloro-phenyl-) propyl group) carbamate (III-Boc) deprotection obtain 2-(3-chloro-phenyl-) third-1-amine (IIId)
To the tertiary butyl-(2-(3-chloro-phenyl-) propyl group) carbamate (III-Boc, 0.8g, add hydrochloric acid (10mL, 6M) in solution 3mmol) in THF (6mL), this reaction system is stirred several hours at 40-45 DEG C.Evaporating solvent, dilute with water organic residue, uses the NaOH aqueous solution by pH regulator to 9, then uses two portions ethyl acetate (40mL) to extract.Use Na 2sO 4dry organic phase, evaporating solvent, obtains oil product (IIId, 0.4g, 78% yield), uses 1h and 13cNMR analyzes confirmation.
1HNMR(500MHz，CDCl 3，ppm)δ8.25(bs，NH 2)，7.25-7.10(m，4ArH)，3.15(m，1H)，2.92(m，2H)，1.15(d，J＝9Hz，3H)；
13CNMR(125MHz，CDCl 3，ppm)δ147.4，134.5，130.0，127.6，126.9，125.7，49.4，43.5，19.4。
Embodiment 9:(S) or the preparation of (R)-2-(3-chloro-phenyl-) third-1-amine ((R)-IIId or (S)-IIId) hydrochloride
At the tertiary butyl-(2-(3-chloro-phenyl-) propyl group) carbamate ((R)-III-Boc or (S)-III-Boc, 2.65g, 9.8mmol) add hydrochloric acid (32mL in cold soln in THF (20mL), 6M), this reaction system is stirred 3 hours at 45 DEG C.Evaporating solvent, dilute with water organic residue, uses the NaOH aqueous solution by pH regulator to 9, then uses two portions ethyl acetate (50mL) to extract.Use Na 2sO 4dry organic phase, evaporating solvent, obtains thick material, then dilutes with ether.Then go through in room temperature and hydrochloric acid (1M, 12mL) was instilled reaction system in 1 hour.After this, cool this reaction system lentamente, wherein salt starts precipitation.Filter out the solid obtained, vacuum-drying ((R)-IIId or (S)-IIId, 1.42g, 71% yield), with NMR spectrography and HPLC analysis and characterization.
1HNMR(500MHz，DMSO，ppm)δ8.30(bs，3H)，7.30-7.15(m，4ArH)，3.18(m，1H)，2.96(m，2H)，1.24(d，J＝9Hz，3H)。
13CNMR(125MHz，DMSO，ppm)δ145.4，133.2，130.5，127.2，126.9，126.1，44.5，37.1，19.2。
IR (sheet): ν=3000-2721 (br), 1597,1572,1505,1466,1393,785,674cm -1.
The synthesis of the chloro-N-of embodiment 10:2-(2-(3-chloro-phenyl-) propyl group) ethanamide (IIIa-Cl)
At cold 2-(3-chloro-phenyl-) third-1-amine (IIId; 250mg, 1.5mmol) at CH 2cl 2(4mL) Na is added in the solution in 2cO 3(1.6mmol), this reaction mixture is stirred 15min at 5-10 DEG C.After this, chloroacetyl chloride (1.6mmol) is instilled this reaction system lentamente, stir several hours at 25 DEG C.This reaction mixture of dilute with water, separation of phases, washs organic phase with salt solution (20mL), uses Mg 2sO 4dry.Solvent evaporated under reduced pressure, obtains oil product (IIIa-Cl, 350mg, 95% yield).
1HNMR(500MHz，CDCl 3，ppm)δ7.30-7.18(m，3ArH)，7.10(m，1ArH)，4.00(s，2H)，3.65(m，1H)，3.34(m，1H)，2.97(m，1H)，1.32(d，J＝8.7Hz，3H)。
13CNMR(125MHz，CDCl 3，ppm)δ166.2，145.8，134.8，130.2，127.5，127.3，125.6，46.4，42.8，39.6，19.0。
IR (only): ν=3291 (br), 1656,1537,1381cm -1.
Optically-active similar compound is also used successfully to carry out identical experiment operation.
The synthesis of the bromo-N-of embodiment 11:2-(2-(3-chloro-phenyl-) propyl group) ethanamide (IIIa-Br)
At cold 2-(3-chloro-phenyl-) third-1-amine (IIId; 1.5mmol) at CH 2cl 2(2mL) iPr is added in the solution in 2etN (3.05mmol), stirs 15min by this reaction mixture at 20 DEG C.After this, bromoacetyl chloride (1.6mmol) is instilled this reaction system lentamente, spend the night 25 DEG C of stirrings.This reaction mixture of dilute with water, separation of phases, washs organic phase with salt solution (20mL), uses Mg 2sO 4dry.Solvent evaporated under reduced pressure, obtains oil product (IIIa-Br, 351mg, 81% yield).
1HNMR(500MHz，CDCl 3，ppm)δ7.28-7.19(m，3ArH)，7.12(m，1ArH)，6.50(bs，NH)，3.76(s，2H)，3.45(m，1H)，3.22(m，1H)，2.89(m，1H)，1.21(d，J＝8.7Hz，3H)。
13CNMR(125MHz，CDCl 3，ppm)δ165.7，145.8，134.8，130.2，127.6，127.4，46.8，42.6，39.6，29.3，19.0。
IR (only): ν=3283,1652,1538,1380,783,695cm -1.
Optically-active similar compound is also used successfully to carry out identical experiment operation.
The synthesis of embodiment 12:2-(3-chloro-phenyl-)-N-(2,2-diethoxy ethyl) third-1-amine (IIIc-Et)
At 2-(3-chloro-phenyl-) third-1-amine (IIId; 480mg, 2.3mmol) add salt of wormwood (643mg, 2 equivalents) and bromoacetaldehyde diethyl acetal (0.4mL, 1.1 equivalents) successively in solution in DMF (10mL).Reaction system is heated to 80 DEG C, stirring is spent the night.Reaction system is cooled to room temperature, with water (40mL) and MTBE (40mL) dilution.Separation of phases, then use MTBE (40mL) aqueous phase extracted.By the organic phase that water (20mL) washing merges, by dried over sodium sulfate, filter, concentrated.Carry out purifying by using reversed-phase column (Systag25-M, C18, the 10-90%MeCN aqueous solution) purifying and obtain pure sample product, obtain 2-(3-chloro-phenyl-)-N-(2,2-diethoxy ethyl) the third-1-amine (IIIc-Et, 227mg, 35%).
1HNMR(500MHz，CDCl 3，ppm)δ7.24-7.13(m，3H)，7.10(d，J＝7.4Hz，1H)，4.54(t，J＝5.6Hz，1H)，3.63(m，2H)，3.47(m，2H)，2.90(hex，J＝7.1Hz，1H)，2.77(d，J＝7.2Hz，2H)，2.72(dd，J＝5.5Hz，J＝12.1Hz，1H)，2.66(dd，J＝5.8Hz，J＝12.1Hz，1H)，1.24(d，J＝6.9Hz，3H)，1.16(t，J＝7.1Hz，3H)，1.14(t，J＝7.1Hz，3H)。
13CNMR(125MHz，CDCl 3ppm)δ147.4，134.3，129.8，127.3，126.5，125.5，101.9，62.4，56.8，52.0，39.9，19.7，16.3。
Optically-active similar compound is also used successfully to carry out identical experiment operation.
The synthesis of embodiment 13:2-(3-chloro-phenyl-)-N-(2,2-dimethoxy-ethyl) third-1-amine (IIIc-Me)
With the dimethoxy acetaldehyde (H of 60% 2o solution, 1.46mL, 2 equivalents) compound 2-(3-chloro-phenyl-) third-1-amine (III of process in methyl alcohol (2mL); 1g, 4.8mmol), by solution stirring at room temperature 48 hours.Add 10%Pd/C (100mg, 10wt%), alternately fill reaction atmosphere several times with nitrogen and hydrogen.Hydrogen pressure is set in 5 normal atmosphere, this reaction system is stirred 4 hours.With filter reaction system, concentrated.Residue is dissolved in DCM (20mL), with 2/1 salt brine solution and HCl1M (20/10mL) washing soln.By dried over sodium sulfate DCM phase, filter, concentrated.Compound is dissolved in toluene (40mL), with water (3 × 30mL) by solution extraction 3 times.With the aqueous phase of the saturated merging of NaCl, with DCM (2 × 30mL) by solution extraction 2 times.By the DCM phase that dried over sodium sulfate merges, filter, concentrated, obtain clean product IIIc-Me, use 1hNMR characterizes.
1HNMR(500MHz，CDCl 3，ppm)δ7.33-7.22(m，3H)，7.18(d，J＝7.2Hz，1H)，4.89(t，J＝5.0Hz，1H)，3.49(m，1H)，3.44(s，3H)，3.42(s，3H)，3.31(m，1H)，3.19(m，1H)，3.08(m，1H)，3.00(m，1H)，1.44(d，J＝6.9Hz，3H)。
The synthesis of embodiment 14:N-(2-chloroethyl)-2-(3-chloro-phenyl-) third-1-amine (IIIb-Cl) hydrochloride
In round-bottomed flask, add the chloro-N-of 2-(2-(3-chloro-phenyl-) propyl group) ethanamide (IIIa-Cl, 2mmol), then add reductive agent BH lentamente 3-THF mixture (the THF solution of 1M; 2.5 equivalents).By this reaction mixture 25 DEG C of vigorous stirring 15 hours.After this, this mixture is cooled to 5 DEG C, uses methyl alcohol quencher, solvent evaporated under reduced pressure.Then dilute organic residue with ether, drip hydrochloric acid.By this reaction mixture at stirring at room temperature 1h, then cool lentamente with precipitate white solid material.White solid (IIIb-Cl, 353mg, 76% yield that vacuum-drying obtains; Mp=160 DEG C), then use 1h and 13cNMR analysis and characterization.
1hNMR (500MHz, CDCl 3+ d 6-acetone, ppm) δ 7.24-7.16 (m, 4ArH), 3.91 (m, 2H), 3.44 (m, 1H), 3.21 (m, 4H), 1.38 (d, J=8.7Hz, 3H).
13cNMR (125MHz, CDCl 3+ d 6-acetone ppm) δ 144,134.9,130.6,127.9,127.4,125.7,54.3,49.3,38.4,36.7,19.9.
IR (sheet): ν=2931,2743,1594,1444,1029cm -1.
Optically-active similar compound is also used successfully to carry out identical experiment operation.
Embodiment 15: N-(2-chloroethyl)-2-(3-chloro-phenyl-) third-1-amine (IIIb) is changed into 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines (A)
Liquid Substrate (IIIb) is added in the test tube installing magnetic stirring bar; 0.5mmol).After this, fresh anhydrous AlCl is added 3(1.75 equivalents, according to raw material), effectively mixes with Liquid Substrate, obtains mashed prod., to 150 DEG C, stirring is spent the night this reaction system to be heated lentamente (10 DEG C/min).Add sodium chloride saturated solution, lentamente cooling reaction system.PH regulator to 9.5-10, then extracts with EtOAC by use 1MNaOH effectively.By the organic phase that salt water washing merges, use Na 2sO 4drying, solvent evaporated under reduced pressure.Use 1the crude mixture that HNMR analysis of spectral method obtains.NMR data are consistent with known references or patent data.
1HNMR(500MHz，CDCl 3)δ7.18(m，ArH)，7.11(m，ArH)，7.00-6.94(m，ArH)，3.20-2.78(m，5H)，2.75(m，1H)，1.29(d，J＝6.8Hz，3H)。
Also use optically-active similar compound successfully to carry out identical experiment method, obtain (S) or (R)-8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines.
The synthesis of embodiment 16:7-chloro-5-methyl-4,5-dihydro-1H-benzo [d] azepines-2-(3H)-one (IVa)
Liquid Substrate (IIIa-Cl, 0.25mmol) is added in the test tube installing magnetic stirring bar.After this, fresh anhydrous AlCl is added 3(0.9mmol), effectively mix with Liquid Substrate, obtain mashed prod.Open reaction system is heated to 80 DEG C lentamente, wherein obtains melting phase, stir 15 minutes at 80 DEG C.Then by this reaction mixture lentamente (5 DEG C/min) be heated to 160 DEG C, stirring is spent the night.Add sodium chloride saturated solution, cool this reaction system lentamente.Then CH is used 2cl 2effectively extract this reaction mixture, the organic phase merged with salt water washing, uses Na 2sO 4drying, solvent evaporated under reduced pressure.Analyze the crude mixture obtained, with GC-MS analysis and characterization/detection compound IVa (m/z:210 (M+1); CI), wherein detect 20%, there is m/z:210 (M+1).
The photochemical syntheses of embodiment 17:7-chloro-5-methyl-4,5-dihydro-1H-benzo [d] azepines-2-(3H)-one (IVa)
By raw material (IIIa-Cl or IIIa-Br, solution 0.25mmol) in the 50%MeCN aqueous solution or the EtOH aqueous solution adds photochemical reactor, under strong stirring, with 100W lamp, (middle pressure Hg-lamp (P=100-150W, λ=main > 300nm) irradiates 1 hour.After evaporating solvent, residue is extracted into ethyl acetate, uses Na 2sO 4drying, solvent evaporated under reduced pressure.Analyze the crude mixture obtained, with GC-MS analysis and characterization/detection compound (m/z:210 (M+1); CI), the compound of 20% expectation wherein detected, there is m/z:210 (M+1).
The synthesis of the chloro-1-oxyethyl group of embodiment 18:7--5-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines (IVc)
Compound III c-Et (113mg, 0.35mmol) is dissolved in DCM (3.5mL), by aluminum chloride (82mg, 1.75 equivalents) treatment soln.By solution in stirred overnight at room temperature.With DCM (20mL) and salt solution (20mL) diluting soln.Separation of phases, then use DCM (10mL) aqueous phase extracted.With the DCM that dried over sodium sulfate merges, filter, concentrated.Analyze the crude mixture obtained, with GC-MS analysis and characterization/detection compound IVc (m/z:240 (M+1); CI), be primary product, and 7-chloro-1-hydroxy-5-methyl base-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines, be secondary product.
Optically-active similar compound is also used successfully to carry out identical experiment method, obtain the chloro-1-oxyethyl group of (S)-or (R)-7--5-methyl-2 respectively, 3,4,5-tetrahydrochysene-1H-benzo [d] azepines and (S)-or (R)-7-chloro-1-hydroxy-5-methyl base-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines.
Embodiment 19:2-(3-chloro-phenyl-) propionitrile is by the preparation of 2-(3-chloro-phenyl-) acetonitrile
In nitrogen atmosphere at-78 DEG C to 2-(3-chloro-phenyl-) acetonitrile VII (66.0mmol; 10.0g) add LiHMDS (66.0mmol in solution in dry THF (250mL); 66.0mL; The THF solution of 1M).This mixture is stirred 1 hour at-78 DEG C, then adds MeI (66.0mmol; 4.2mL).After stirring 1 hour at-78 DEG C, this reaction mixture is warmed to room temperature, stirs 2 hours.Make this reaction mixture quencher with water (200mL), extract with EtOAc (3x150mL).Use MgSO 4the dry organic phase merged, filters, is evaporated to dry.By (silica gel after purified by flash chromatography; Moving phase: normal heptane/EtOAc, EtOAc gradient 2-20%), obtain oil product VIII (7.6g; 72%).
1HNMR(500MHz，CDCl 3，ppm)δ7.34(m，3H)，7.26(m，1H)，3.89(q，1H，J＝7.2Hz)，1.65(d，3H，J＝7.4Hz)；
13CNMR(125MHz，CDCl 3，ppm)δ138.9，135.0，130.5，128.4，127.0，125.0，121.0，31.0，21.3。
Embodiment 20:2-(3-chloro-phenyl-) third-1-amine is by the preparation of 2-(3-chloro-phenyl-) propionitrile
In nitrogen atmosphere at 0 DEG C to 2-(3-chloro-phenyl-) propionitrile VIII (45.3mmol; BH is added in solution 7.5g) in toluene (150mL) 3.THF (135.8mmol; 135.8mL, 1M).This reaction mixture refluxed is stirred 4 hours.After being cooled to room temperature, make this reaction mixture quencher with water (150mL), then use EtOAc (1x300mL) to extract.Use MgSO 4dry organic phase, filters, passes through evaporation of solvent.By with HCl (Et 2o solution) process residue separation pure products, be hydrochloride, 70% yield (6.6g).
1HNMR(500MHz，CDCl 3，ppm)δ7.22(m，3H)，7.08(d，1H)，2.83(m，2H)，2.72(m，1H)，1.23(d，1H)，1.08(bs，NH)；
13CNMR(125MHz，CDCl 3，ppm)δ145.4，133.2，130.5，127.2，126.9，126.1，44.5，37.1，19.2。
Embodiment 21: use (R)-(-)-2-phenylpropionic acid to the optical resolution of 2-(3-chloro-phenyl-) third-1-amine
At 70 DEG C to 2-(3-chloro-phenyl-) third-1-amine III (3.0mmol; (R)-(-)-2-phenylpropionic acid (1.5mmol is added in solution 0.5g) in EtOH (3mL); Solution 0.2g) in EtOH (1mL).This reaction mixture is stirred 30min at 70 DEG C, then in several hours, is cooled to room temperature.Stir after 16 hours, filter the precipitation obtained, with EtOH washing, drying under reduced pressure, obtains 0.29g salt III-PP (chirality HPLC:74.1%ee, R-enantiomorph).
Recrystallization:
EtOH (3mL) is dissolved at 70 DEG C of salt obtained by 0.28g.This solution is stirred 30min at 70 DEG C, then in several hours, is cooled to room temperature.Stir after 16 hours, filter the precipitation obtained, with EtOH washing, drying under reduced pressure, obtains 0.19g salt (R)-III-PP (chirality HPLC:98.1%ee, R-enantiomorph).
Embodiment 22: use L-(-)-PLA to the optical resolution of 2-(3-chloro-phenyl-) third-1-amine
At 70 DEG C to 2-(3-chloro-phenyl-) third-1-amine III (4.1mmol; L-(-)-PLA (2.1mmol is added in solution 0.7g) in toluene (5mL); 0.3g).This reaction mixture is stirred 30min at 70 DEG C, then in several hours, is cooled to room temperature.Stir after 16 hours, filter the precipitation obtained, with toluene wash, drying under reduced pressure, obtain 0.44gIII-lactic acid salt (chirality HPLC:80.5%ee, R-enantiomorph).
Recrystallization:
I-PrOH (2mL) is dissolved at 70 DEG C of salt obtained by 0.43g.This solution is stirred 30min at 70 DEG C, then in several hours, is cooled to room temperature.Stir after 16 hours, filter the precipitation obtained, with i-PrOH washing, drying under reduced pressure, obtains 0.23g (R)-III-lactic acid salt (chirality HPLC:96.7%ee, R-enantiomorph).
Optionally by with Na 2cO 3solution washing ethyl acetate solution, then by evaporation of solvent, lactic acid salt is changed into alkali.
Embodiment 23:(R) preparation of-2-(3-chloro-phenyl-)-N-(2,2-dimethoxy-ethyl) third-1-amine hydrochlorate
With the dimethoxy acetaldehyde (H of 60% 2o solution, 1.46mL, 2 equivalents) (R)-2-(3-chloro-phenyl-) third-1-amine (the R)-III (1g, 4.8mmol) of process in methyl alcohol (2mL), by this solution stirring at room temperature 48 hours.Add 10%Pd/C (100mg, 10wt%), alternately fill reaction atmosphere several times with nitrogen and hydrogen.Hydrogen pressure is set in 1 normal atmosphere, this reaction system is stirred 4 hours.With filter this reaction system, concentrated.Residue is dissolved in CH 2cl 2(20mL), this solution is washed with 2: 1 salt brine solutions and HCl1M (20/10mL).Use dried over sodium sulfate CH 2cl 2phase, filters, concentrated.Residue is dissolved in toluene (40mL), with water (3 × 30mL) by this solution extraction 3 times.With the aqueous phase of the saturated merging of NaCl, use CH 2cl 2(2 × 30mL) is by this solution extraction 2 times.With the CH that dried over sodium sulfate merges 2cl 2phase, filters, concentrated, obtains clean product (R)-IIIc-Me.HCl, uses 1hNMR characterizes.
1HNMR(500MHz，CDCl 3，ppm)δ7.33-7.22(m，3H)，7.18(d，J＝7.2Hz，1H)，4.89(t，J＝5.0Hz，1H)，3.49(m，1H)，3.44(s，3H)，3.42(s，3H)，3.31(m，1H)，3.19(m，1H)，3.08(m，1H)，3.00(m，1H)，1.44(d，J＝6.9Hz，3H)。
Embodiment 24:(R)-N-(2-(3-chloro-phenyl-) propyl group)-N-(2,2-dimethoxy-ethyl)-4-methyl benzenesulfonamide is by the synthesis of 2-(3-chloro-phenyl-)-N-(2,2-dimethoxy-ethyl) third-1-amine
By 2-(3-chloro-phenyl-) third-1-amine (R)-IIIc-Me (2.95mmol; 0.76g) at CH 2cl 2solution in/pyridine (8/1,4.2mL) is cooled to 0 DEG C, after this, adds TsCl (5.31mmol; 1.0g) at CH 2cl 2(1.8mL) solution in.This reaction mixture is warmed to room temperature, stirs 2.5 hours.With 2MHCl (2x4.3mL) and saturated NaHCO 3the aqueous solution (4.3mL) washs this reaction mixture.Use MgSO 4dry organic layer, filters, reduction vaporization, to remove desolventizing.By purified by flash chromatography residue (elutriant: EtOAc/ normal heptane, EtOAc gradient 7-60%).Obtain colorless oil as product (R)-IIIc '-Me-Ts (0.85g; 71% yield), use 1h and 13cNMR characterizes.
1HNMR(500MHz，CDCl 3，ppm)δ7.64(d，2H)，7.28(d，2H)，7.19(m，2H)，7.08(m，2H)，4.43(t，1H)，3.45(m，1H)，3.36(d，6H)，3.13(m，4H)，2.42(s，3H)，1.25(d，3H)；
13CNMR(125MHz，CDCl 3，ppm)δ146.2，143.4，136.6，134.2，129.8，129.7，127.6，127.2，126.7，125.5，104.6，56.5，55.3，55.1，50.8，38.2，21.5，18.6。
The chloro-1-methyl of embodiment 25:8--3-tosyl group-2,3-dihydro-1H-benzo [d] azepines is by the synthesis of N-(2-(3-chloro-phenyl-) propyl group)-N-(2,2-dimethoxy-ethyl)-4-methyl benzenesulfonamide
By N-(2-(3-chloro-phenyl-) propyl group)-N-(2,2-dimethoxy-ethyl)-4-methyl benzenesulfonamide IIIc '-Me-Ts (2.1mmol in nitrogen atmosphere; 0.85g) at CH 2cl 2(10mL) solution in joins AlCl 3(8.3mmol; 1.1g) at CH 2cl 2(15mL) in the suspension in.By this reaction mixture at stirring at room temperature 10min, be then cooled to 0 DEG C.With 1MNaOH (11mL) and H 2after O (11mL) quencher, separation of phases.Use CH 2cl 2(3x15mL) aqueous phase extracted.Use MgSO 4the dry organic phase merged, filters, passes through evaporation of solvent.Obtain yellow solid product IV '-Ts (0.6g; 85% yield), use 1h and 13cNMR characterizes.
1HNMR(500MHz，CDCl 3，ppm)δ7.72(d，2H)，7.32(d，2H)，7.10(m，1H)，7.05(m，2H)，6.89(dd，1H)，5.55(d，1H)，4.06(m，1H)，3.14(m，2H)，2.42(s，3H)，1.17(d，3H)；
13CNMR(125MHz，CDCl 3，ppm)δ145.3，144.2，135.8，132.2，131.8，131.5，130.0，129.4，128.1，127.0，126.6，126.1，107.4，50.3，40.1，21.6，18.0。
Embodiment 26: synthesize the chloro-1-methyl of 8--3-tosyl group-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines by 8-chloro-1-methyl-3-tosyl group-2,3-dihydro-1H-benzo [d] azepines
To the chloro-1-methyl of 8--3-tosyl group-2,3-dihydro-1H-benzo [d] azepines IV '-Ts (0.54mmol; PtO is added in solution 0.19g) in methyl alcohol (3mL) 2(20mg) with several HCl.This reaction mixture is stirred 48 hours in 5 bar hydrogen atmospheres at 25 DEG C.Pass through pad passes through solvent removed by evaporation at reduced pressure after filtering.Residue is dissolved in EtOAc (6mL), with water (6mL) washing, uses MgSO 4drying, filters, is evaporated to dry.By (elutriant: normal heptane/EtOAc, EtOAc gradient 7-60%) after purified by flash chromatography, use 1h and 13cNMR characterizes product.
1HNMR(500MHz，CDCl 3，ppm)δ7.62(d，2H)，7.27(d，2H)，7.07(m，2H)，7.05(m，2H)，6.97(d，1H)，3.28-2.92(m，6H)，2.40(s，3H)，1.40(d，3H)；
13CNMR(125MHz，CDCl 3，ppm)δ146.0，143.3，137.8，135.2，132.4，131.3，129.7，127.5，127.1，126.3，53.5，48.1，40.0，35.9，21.5，17.5。
Embodiment 27: synthesize 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines by the chloro-1-methyl of 8--3-tosyl group-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines
By chloro-for 8-1-methyl-3-tosyl group-2; 3; 4; 5-tetrahydrochysene-1H-benzo [d] azepines A '-Ts (0.17mmol; 59mg), the reaction mixture refluxed of phenol (0.55mmol, 53mg), 48%HBr (0.45mL) and propionic acid (0.09mL) stirs 6 hours.After being cooled to room temperature, making this reaction mixture quencher with water (2mL), then use Et 2o (2x5mL) extracts.To alkalize aqueous phase (pH>=9) with 8MNaOH, use CH 2cl 2(3x5mL) extraction product.Use MgSO 4the dry organic phase merged, filters, is evaporated to dry.The product (m/z=195) obtained is detected by GC-MS.

Claims (20)

1. for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydrochysene-1H-benzo [d] azepines of following formula A example or the method for its salt:
* in its Chinese style represents asymmetric C atom, and the method comprises the following step:
A () is by the compound of following formula I:
Change into the cyclic sulfonamides compound compound of Formula Il:
R in its Chinese style II is amino protecting group, and it is preferably from-Boc (tertbutyloxycarbonyl) ,-Cbz (carbobenzoxy) ,-Bz (benzoyl) ,-Bn (benzyl) ,-Ac (ethanoyl) or-CH 2cH (OR 2) 2(wherein R 2the alkyl with 1-6 carbon atom, preferable methyl or ethyl, or two R 2c2-or C3-alkylidene chain can be bonded to together, form 5-or 6-ring);
B the converting compounds of formula II is become the compound of Formula Il I by ():
R wherein in formula III with above-mentioned formula II is defined identical; With
C the converting compounds of formula III becomes by ()
(c-1) compound of Formula Il Ia:
X wherein in formula III a is suitable for the leaving group of intramolecular cyclization Friedel-Craft Er Shi alkylated reaction or compatibly can be converted to the group of this kind of leaving group, and wherein X is preferably-OH, tolylsulfonyl ester, methanesulfonates, triflate or is selected from the halogen of Cl, Br, I, and wherein X most preferably Cl or Br;
Or
(c-2) compound of Formula Il Ib:
X wherein in formula III b with the compound of above-mentioned formula III a is defined identical;
Or
(c-3) compound of Formula Il Ic:
Wherein R 2with above-mentioned formula II is defined identical;
Wherein R* is amino protecting group;
Wherein can ignore the formation of the compound of formula III c for following situation: the R in the compound of above-mentioned formula II and III has been expressed as-CH defined above 2cH (OR 2) 2;
With;
D the converting compounds of formula III a or formula III b or formula III c or formula III e is become the compound of above-mentioned formula A by () through the following steps:
(d-1) intramolecular cyclization reaction is carried out, preferred intramolecular cyclization friedel-Crafts reaction or photochemically-induced ring-closure reaction;
(d-2) if optionally and be applicable to, reduction reaction; With
(d-3) if optionally and be applicable to, deprotection reaction.
2. method according to claim 1, wherein step (a) comprises the following step:
(a-1) converting compounds of formula I is become the compound of following formula V:
R in its Chinese style V with above-mentioned formula II is defined identical;
With
(a-2) converting compounds of formula V is become the compound of above-mentioned formula II,
Wherein step (a-2) optionally comprises:
(a-2-1) converting compounds of formula V is become the compound of following formula VI:
R in its Chinese style VI with above-mentioned formula V is defined identical; With
(a-2-2) compound of oxidation-type VI subsequently, obtains the compound of formula II, is not preferably separated midbody compound VI;
With
Wherein preferably make the compound of the formula I in step (a-1) and be selected from following reagent react:
(i) chloroformic acid benzyl ester, (PhCH 2oCO) 2o or N α-(carbobenzoxy-(Cbz) oxygen base) succinimide, for introducing-Cbz;
(ii) two di-tert-butyl carbonate, for introducing-Boc;
(iii) Benzoyl chloride, for introducing-Bz;
(iv) benzyl chloride or bromotoluene, for introducing-Bn;
V () acetic anhydride or Acetyl Chloride 98Min., for introducing-Ac;
(vi) X 3cH 2cH (OR 2) 2or OHC-CH (OR 2) 2, wherein X 3tolylsulfonyl ester, methanesulfonates, triflate or halogen, preferred Cl or Br, and R 2with as above-mentioned define identical, for introducing-CH defined above 2cH (OR 2) 2(wherein R 2with as above-mentioned define identical);
And/or
Wherein step (a-2-2) preferably comprises the compound by using oxidizing formula VI, and described oxygenant is selected from RuO 2, NaIO 4, H 2o 2, urea-H 2o 2, cumene H 2o 2, m-CPBA (m-chlorine peroxybenzoic acid), NaBO 3xH 2o, MnO 2and ozone, preferred NaIO 4and RuO 2.
3., according to the method for claim 1 or 2, wherein make the compound of the formula II in step (b) and the compound of following formula VII react:
M in its Chinese style VII is selected from Li, MgBr and MgCl, preferred MgCl; And wherein this reaction preferably by CuX (X=Cl, Br, I), ZnCl 2, FeCl 3catalysis, more preferably by CuI or CuCl catalysis, and particularly preferably by CuI catalysis, wherein M=MgCl.
4., according to the method for any one of claim 1-3, wherein step (c) also comprises:
For step (c-1):
(c-1-1) if R right and wrong-CH defined above 2cH (OR 2) 2group, then remove radicals R from the compound of formula III, obtain the compound of Formula Il Id:
With
(c-1-2) compound of formula III d is made to react with the compound being expressed as following formula VIII:
Wherein X 1be selected from OH, F, Cl and Br, preferred Cl, and X 2be selected from OH, Cl and Br, and preferred Cl or Br,
Obtain the compound of formula III a, if wherein-X 2this hydroxyl of=OH-can be converted to tosylate, methanesulfonates, triflate, one of Cl, Br or I further, preferably changes into Cl or Br, if and/or condition be-X 1this hydroxyl of=OH-is activated, and forms amido linkage;
For step (c-2):
(c-2-1)-similar reactions steps (c-1-1) and (c-1-2) afterwards-subsequently with the amido linkage of the compound of the reductive agent reduction-type IIIa be applicable to, described reductive agent is preferably selected from LiAlH 4, RED-Al, DIBAL-H, diboron hexahydride, BH 3-THF mixture or hydride, obtain the compound of formula III b; Or
(c-2-2)-similar removing step (c-1-1) afterwards-make the compound of formula III d react with the compound being expressed as following formula I X subsequently:
Wherein X 2with above-mentioned formula VIII is defined identical,
Use applicable reductive agent in one pot of reductive amination reaction, obtain the compound of formula III b, described applicable reductive agent is preferably selected from H 2/ Pd/C/HCl, sodium borohydride, sodium cyanoborohydride and sodium triacetoxy borohydride, condition is if X 2=OH, this hydroxyl can be converted to tosylate, methanesulfonates, triflate, one of Cl, Br or I further, preferably changes into Cl or Br;
For step (c-3):
(c-3-1) if the R in the compound of-above-mentioned formula III is not yet expressed as-CH defined above 2cH (OR 2) 2, then similar removing step (c-1-1) afterwards-make subsequently the compound of formula III d be expressed as formula X defined above 3cH 2cH (OR 2) 2compound (wherein X 3preferred Cl or Br, and R 2preferable methyl or ethyl) or OHC-CH (OR 2) 2(wherein R 2preferable methyl or ethyl) reaction, obtain the compound of formula III c, or
(c-3-2) if the R in the compound of-above-mentioned formula III is not yet expressed as-CH defined above 2cH (OR 2) 2, then make the compound of formula III and be expressed as formula X defined above 3cH 2cH (OR 2) 2compound (wherein X 3preferred Cl or Br, and R 2preferable methyl or ethyl) or OHC-CH (OR 2) 2(wherein R 2preferable methyl or ethyl) reaction, obtain the compound of formula III e, wherein R* and R is identical,
(c-3-3) if the R in the compound of-above-mentioned formula III has been expressed as-CH defined above 2cH (OR 2) 2the preferred trityl of methyl (Tr) that then amino with protecting group protection, described protecting group is preferably selected from unsubstituted benzyl (Bn) or the preferred Alpha-Methyl replaced, p-nitro, p-methyl or the benzyl (PMB) of p-methoxy substitution, many phenyl replace, the unsubstituted or C that fluoridizes 1-C 4preferred methylsulfonyl (the methylsulfonyl of-alkane alkylsulfonyl; or trifyl (trifyl Ms); Tf), or preferred p-methyl (tosyl group, Ts) that is unsubstituted or para-orientation replace benzenesulfonyl, unsubstituted or replace C 1-C 6the preferred ethanoyl of-alkyloyl (Ac) or the preferred benzoyl of aryl carbonyl (Bz); obtain the compound of formula III e; wherein R* is expressed as described group, is preferably expressed as-Bn ,-PMB ,-Tr ,-Ms ,-Tf ,-Ts ,-Ac or-Bz.
5. according to the method for any one of claim 1-4, wherein
Intramolecular cyclization reaction in step (d/d-1) carries out in the case where there: (i) at Lewis acid or under the existence of acid, described Lewis acid is selected from AlCl 3, FeCl 3, InCl 3, InBr 3, Bi (OTf) 3, BiCl 3, Sc (OTf) 3, TeCl 4, BF 3× OEt 2, preferred anhydrous AlCl 3; Described acid is selected from HOTf, pTsOH, TFA, CH 3sO 3h, H 3pO 4/ P 2o 5, H 2sO 4/ AcOH mixture, dense H 2sO 4or Tripyrophosphoric acid (PPA), and preferred H 2sO 4or PPA; Or (ii)-for the compound-optionally by photochemically-induced ring-closure reaction of formula III a and IIIb, obtain:
(d-1-1) if the compound of the compound-following formula I Va of-cyclisation formula III a:
(d-1-2) if the compound of the compound-Shi A of-cyclisation formula III b;
(d-1-3) if the compound of-cyclisation formula III c or IIIe, the compound of following formula I Vc, IVd or IVe or its mixture:
Wherein R 3h, methyl or ethyl, and R* with define in c-3-2 or c-3-3 of clause 6 identical, and
And the reduction in the step (d-2) needed for compound of wherein only formula IVa, IVc, IVd and IVe is undertaken by using applicable reductive agent, described applicable reductive agent is preferably selected from: BH 3mixture, H 2/ metal catalyst (preferred Rh, Ru, Pd), NaBH 4/ H 2sO 4, LiAIH 4, Et 3n/HCOOH, RED-Al, DIBAL-H, H 2/ Pd/C/HCl or Zn/HCl, and most preferably BH 3-THF mixture or hydride, for the compound of reduction-type IVa; And H 2/ Pd/C/HCl, H 2/ PtO or Zn/HCl, for the compound of reduction-type IVc; And H 2/ PtO, for the compound of respectively reduction-type IVd or IVe, and if optionally obtain the compound of formula A after the compound formation deprotection of formula IVe.
6. according to the method for any one of claim 1-5, wherein
The method is carried out through the following steps:
(a-1) by the compound (wherein R is preferably-Boc) of the converting compounds accepted way of doing sth V of formula I;
(a-2-1) make the compound of formula V and thionyl chloride react and (a-2-2) with rear oxidation (preferably by using NaIO 4and RuO 2) midbody compound of formula VI, obtain the compound of formula II;
B () carries out the ring-opening reaction similar with claim 5, wherein preferred by CuI catalysis, M=MgCl, obtains the compound of formula III;
(c-1) removing R by (c-1-1) reacts the compound (wherein X=Cl, Br) of the converting compounds accepted way of doing sth IIIa of formula III with (c-1-2) and bromoacetyl chloride or chloroacetyl chloride, obtain the compound of formula III a, wherein X=Br or Cl;
(d-1-1) by friedel-Crafts reaction, the preferably anhydrous AlCl of use 3or by the compound of photochemically-induced ring-closure reaction cyclisation formula III a, obtain the compound of formula IVa;
(d-2) preferably BH is used 3the compound of-THF mixture or hydride reduction formula IVa, obtains the compound of formula A;
Or
Wherein the method is carried out through the following steps:
(a-1) by the compound (wherein R is preferably-Boc) of the converting compounds accepted way of doing sth V of formula I;
(a-2-1) make the compound of formula V and thionyl chloride react and (a-2-2) with rear oxidation (preferably by using NaIO 4and RuO 2) midbody compound of formula VI, obtain the compound of formula II;
B () carries out the ring-opening reaction similar with claim 5, wherein preferred by CuI catalysis, M=MgCl, obtains the compound of formula III;
(c-2) remove R by (c-2-1) and react the compound (wherein X=Cl, Br) of the converting compounds accepted way of doing sth IIIb of formula III with bromoacetyl chloride or chloroacetyl chloride, obtaining the compound of formula III a, wherein X=Br or Cl; (c-2-2) subsequently with the amido linkage of the compound of the reductive agent reduction-type IIIa be applicable to, described applicable reductive agent is preferably selected from LiAlH 4, RED-Al, DIBAL-H, diboron hexahydride, BH 3* THF mixture or hydride, most preferably BH 3* THF mixture;
(d-1-2) by friedel-Crafts reaction, the preferably anhydrous AlCl of use 3or by the compound of photochemically-induced ring-closure reaction cyclisation formula III b, obtain the compound of formula A;
Or
Wherein the method is carried out through the following steps:
(a-1) preferably by making the compound of formula I and being selected from 2-bromo-1,1-glycol dimethyl ether, 2-bromo-1,1-diethoxyethane, 2,2-dimethoxy acetaldehyde and 2, a kind of compound reaction of 2-diethoxy acetaldehyde is by the compound of the converting compounds accepted way of doing sth V of formula I, and wherein R is-CH defined above 2cH (OR 2) 2;
(a-2-1) make the compound of formula V and thionyl chloride react and (a-2-2) with rear oxidation (preferably by using NaIO 4and RuO 2) midbody compound of formula VI, obtain the compound of formula II;
B () carries out the ring-opening reaction similar with claim 5, wherein preferred by CuI catalysis, M=MgCl, obtains the compound of formula III c, middle OR 2define as above-mentioned;
(d-1-3) by friedel-Crafts reaction, the preferably anhydrous AlCl of use 3, dense H 2sO 4or the compound of PPA cyclisation formula III c, obtain the compound of formula IVc;
(d-2) preferably H is used 2the compound of/Pd/C/HCl or Zn/HCl reduction-type IVc, obtains the compound of formula A;
Or
Wherein the method is carried out through the following steps:
(a-1) by the compound (wherein R is preferably-Boc) of the converting compounds accepted way of doing sth V of formula I;
(a-2-1) make the compound of formula V and thionyl chloride react and (a-2-2) with rear oxidation (preferably by using NaIO 4and RuO 2) midbody compound of formula VI, obtain the compound of formula II;
B () carries out the ring-opening reaction similar with claim 5, wherein preferred by CuI catalysis, M=MgCl, obtains the compound of formula III;
(c-3) by (c-3-1) remove R and with above-mentioned formula X 3cH 2cH (OR 2) 2compound (wherein X 3preferred Cl or Br, and R 2preferable methyl or ethyl) or OHC-CH (OR 2) 2(wherein R 2preferable methyl or ethyl) react the compound of the converting compounds accepted way of doing sth IIIc of formula III;
(d-1-3) by friedel-Crafts reaction, the preferably anhydrous AlCl of use 3, dense H 2sO 4or the compound of PPA cyclisation formula III c, obtain the compound of formula IVc or IVd;
(d-2) preferably H is used 2the compound of/Pd/C/HCl or Zn/HCl reduction-type IVc and preferably use H 2the compound of/PtO reduction-type IVd, obtains the compound of formula A.
7. according to the method for any one of claim 1-6, wherein the method is Stereoselective synthesizing process, and it produces
Substantially i the enantiomer-pure of the compound of () formula A or the R enantiomorph of enantiomer-pure or its salt, be expressed as following formula (R)-A or its salt:
Wherein said stereoselective syntheses is from the enantiomer-pure substantially of compound of formula I being expressed as following formula (R)-I or the R enantiomorph of enantiomer-pure:
And wherein said synthesis is carried out with stereoselective manner by the R enantiomorph of the enantiomer-pure substantially or enantiomer-pure that are expressed as the compound of the formula II of following formula (R)-II:
The compound of its Chinese style (R)-II is converted to the enantiomer-pure substantially of the compound of the formula III being expressed as following formula (R)-III or the R enantiomorph of enantiomer-pure in step (b):
And wherein subsequently chirality be retained in building-up process, produce the enantiomer-pure substantially of following formula (R)-A or the chipal compounds of enantiomer-pure or its salt;
Or
(ii) enantiomer-pure substantially of the compound of formula A or the S enantiomorph of enantiomer-pure or its salt, is expressed as following formula (S)-A or its salt:
Wherein said stereoselective syntheses is from the enantiomer-pure substantially of compound of formula I being expressed as following formula (S)-I or the S enantiomorph of enantiomer-pure:
And wherein said synthesis is carried out with stereoselective manner by the S enantiomorph of the enantiomer-pure substantially or enantiomer-pure that are expressed as the compound of the formula II of following formula (S)-II:
The compound of its Chinese style (S)-II is converted to the enantiomer-pure substantially of the compound of the formula III being expressed as following formula (S)-III or the S enantiomorph of enantiomer-pure in step (b):
And wherein subsequently chirality be retained in building-up process, produce the enantiomer-pure substantially of following formula (S)-A or the chipal compounds of enantiomer-pure or its salt.
8. according to formula III ' compound or its salt:
Wherein formula III ' in R ' be expressed as: (i) R defined above; it is amino protecting group, is preferably selected from-Boc (tertbutyloxycarbonyl) ,-Cbz (carbobenzoxy) ,-Bz (benzoyl) ,-Bn (benzyl) ,-Ac (ethanoyl) or-CH 2cH (OR 2) 2(wherein R 2the alkyl with 1-6 carbon atom, preferable methyl or ethyl or two R 2c2-or C3-alkylidene chain can be bonded to together, form 5-or 6-ring) or be expressed as (ii)-H ,-COCH 2x or-CH 2cH 2-X (wherein X defines and preferably-OH, tosylate, methanesulfonates, triflate or halogen as above-mentioned, preferred Cl, Br or I, and wherein X most preferably Cl or Br);
And be preferably expressed as:
The compound (in formula III defined above R=H) of (i) formula III defined above d;
Or
(ii) compound (preferred X is expressed as Cl, Br or I, more preferably Cl or Br) of formula III a defined above;
Or
(iii) compound (preferably wherein X is expressed as Cl, Br or I, more preferably Cl or Br) of formula III b defined above;
Or
(iv) compound (the preferably wherein R of above-mentioned formula III c 2for methyl or ethyl).
9. compound according to claim 8, it is:
(i) formula III ' the enantiomer-pure substantially of compound or the R enantiomorph of enantiomer-pure, be expressed as following formula (R)-III ' or its salt:
R ' wherein in compound (R)-III ' with define in claim 8 identical;
Or
(ii) formula III ' the enantiomer-pure substantially of compound or the S enantiomorph of enantiomer-pure, be expressed as following formula (S)-III ' or its salt:
R ' wherein in compound (S)-III ' with define in claim 8 identical.
10. for the production of according to Claim 8 or 9 the method for compound, wherein the method comprise as any one of claim 1,3,6 or 7 the reactions steps (b) that defines, the method optionally also comprise as any one of claim 1,4,6 or 7 define reactions steps (c), (c-1), (c-2), (c-3), (c-1-1), (c-1-2), (c-2-1), (c-2-2) and (c-3-1) one or more.
The compound that 11. formula IVa represent:
It can be racemic, enantiomer-pure or enantiomer-pure substantially R or S type, and it is preferably the R type (formula (R)-IVa) of enantiomer-pure or enantiomer-pure substantially.
The compound or its salt that 12. formula IVc represent:
It can be racemic, enantiomer-pure or enantiomer-pure substantially R or S type, wherein R 2define as above-mentioned and be preferably methyl or ethyl, and this compound is preferably the R type (formula (R)-IVc) of enantiomer-pure or enantiomer-pure substantially.
13. for the production of the method for the compound according to claim 11 or 12, wherein the method comprises:
(i) as any one of claim 1,5,6 or 7 the reactions steps (d-1) that defines and/or (d-1-1), for the production of the compound that formula IVa represents;
Or
(ii) as any one of claim 1,5,6 or 7 the reactions steps (d-1) that defines and/or (d-1-3), for the production of the compound that formula IVc represents.
14. formula II " compound represented:
Its Chinese style II " in R " is expressed as-CH defined above 2cH (OR 2) 2(wherein R 2methyl or ethyl or two R 2c2-or C3-alkylidene chain can be bonded to together, form 5-or 6-ring), this compound can be racemic, enantiomer-pure or enantiomer-pure substantially R or S type, and it is preferably R type (formula (the R)-II ") of enantiomer-pure or enantiomer-pure substantially.
15. for the production of the method for compound according to claim 14, wherein the method comprise as any one of claim 1,2,6 or 7 the reactions steps (a) that defines and/or (a-1) and/or (a-2) and/or (a-2-1) and/or (a-2-2).
16. according to Claim 8,9,11, the compound of 12 or 14 any one has purposes in the diet pill of 8-chloro-1-methyl-benzo [d] azepines skeleton in preparation, it is preferably chlorine Ka Selin or its salt.
17. compounds according to claim 9, wherein the compound of (i) is expressed as the compound according to above-mentioned formula (R)-IIId, is the salt form with chiral organic acid.
a* is chiral anion
The compound of 18. formulas (R)-2-(3-chloro-phenyl-) third-1-ammonium (R)-(-)-2-phenylpropionic acid salt.
The compound of 19. formulas (R)-2-(3-chloro-phenyl-) third-1-ammonium (L)-(-)-phenyl-lactic acid salt.
20. compounds according to claim 9, wherein the compound of (ii) is expressed as the compound of above-mentioned formula (S)-IIId, is the salt form with chiral organic acid.
a* is chiral anion
CN201480035262.XA 2013-04-23 2014-04-23 Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof Pending CN105358534A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP13164994.9 2013-04-23
EP13164994 2013-04-23
PCT/EP2014/058194 WO2014173928A1 (en) 2013-04-23 2014-04-23 Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof

Publications (1)

Publication Number Publication Date
CN105358534A true CN105358534A (en) 2016-02-24

Family

ID=48141864

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201480035262.XA Pending CN105358534A (en) 2013-04-23 2014-04-23 Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof

Country Status (3)

Country Link
EP (1) EP2989082A1 (en)
CN (1) CN105358534A (en)
WO (1) WO2014173928A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109574859A (en) * 2018-11-26 2019-04-05 山东省科学院新材料研究所 A kind of synthetic method of BETTY BOOP alkali derivant

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUE045208T2 (en) 2014-01-24 2019-12-30 Turning Point Therapeutics Inc Diaryl macrocycles as modulators of protein kinases
WO2017004342A1 (en) 2015-07-02 2017-01-05 Tp Therapeutics, Inc. Chiral diaryl macrocycles as modulators of protein kinases

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1575495A4 (en) * 2002-03-27 2009-12-02 Smithkline Beecham Corp Compounds and methods
ES2571220T3 (en) * 2003-06-17 2016-05-24 Arena Pharm Inc 8-Chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride
CN102933556B (en) * 2010-06-03 2015-08-26 拜尔农科股份公司 N-[(mixing) aryl ethyl] pyrazoles (sulfo-) carboxylic acid amides and the assorted analogue replaced thereof
AR088989A1 (en) * 2011-11-30 2014-07-23 Hoffmann La Roche BICYCLE DERIVATIVES OF DIHYDROISOQUINOLIN-1-ONA

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109574859A (en) * 2018-11-26 2019-04-05 山东省科学院新材料研究所 A kind of synthetic method of BETTY BOOP alkali derivant

Also Published As

Publication number Publication date
WO2014173928A1 (en) 2014-10-30
EP2989082A1 (en) 2016-03-02

Similar Documents

Publication Publication Date Title
CN101284837B (en) Stereoselective total synthesis method of (+)-biotin
CN104520275B (en) For preparation method and the intermediate product of integrase inhibitor
CN102336754B (en) Method for synthesizing entecavir and intermediate compound thereof
BR112021003061A2 (en) process for the preparation of 6-(2,4-dichlorophenyl)-5-[4-[(3s)-1-(3-fluoropropyl)pyrrolidin-3-yl]oxyphenyl]-8,9-dihydro-7h-benzo methyl [7]annulene-2-carboxylate
JPH0432831B2 (en)
CN103772193B (en) Prepare the method for tricyclic derivatives
CN105358534A (en) Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine, novel intermediates and the production thereof
CN101107228B (en) Process for producing (Z)-1-phenyl-1-(N,N-diethylaminocarbonyl)-2-phthalimidomethylcyclopropane
CN102174015A (en) Refining method of rebamipide
CN107417595A (en) A kind of synthetic method of serial monoterpenoid indole alkaloid skeleton and natural products based on free radical cascade reaction
CN104974167B (en) The preparation method of asenapine and the intermediate for being used to prepare asenapine
CN109574906A (en) A kind of preparation method of 3,3 '-two Indoleacetic esters
WO2007011162A1 (en) Synthetic method of optically pure (s)-3-hydroxypyrrolidine
PL117107B1 (en) Process for preparing novel 4a,9b-trans-5-aryl-2,3,4,4a,5,9b-hexahydro-1h-pyrido/4,3-b/indoles-geksagirdid 1h-pirido 4,3-b ionidolov
CN107935866B (en) Preparation method of dapoxetine hydrochloride impurity
CN104203915B (en) (3,4 Dichlorobenzene base) ((S) 3 propyl pyrrole alkane 3 base) methanone hvdrochloric acid salt and manufacture method
Osorio-Olivares et al. A two-step method for the preparation of homochiral cathinones
CN103517897A (en) Synthesis of cyclopentaquinazolines
Thomas et al. A tandem highly stereoselective FeCl3-promoted synthesis of a bisindoline: Synthetic utility of radical cations in heterocyclic construction
CN105294828B (en) The preparation method of Ao Beitawei
US8143400B2 (en) Process for the preparation and purification of cis-2-methylspiro(1,3-oxathiolane-5,3′)quiniclidine hydrochloride
CN113387955A (en) 1,2,3, 4-tetrahydrocinnoline framework compound and synthetic method thereof
CA1137489A (en) Derivatives of 1,2,3,3a,8,8a-hexadydropyrrolo (2,3-b) indole
TW200408635A (en) Optically active β-aminoketones, optically active 1, 3-amino alcohols and processes for preparing them
CN110862367A (en) Coumarin aryl ether compound and preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20160224