CN109748767A - A method of deuterated aminated compounds is prepared using microwave reaction device - Google Patents
A method of deuterated aminated compounds is prepared using microwave reaction device Download PDFInfo
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Abstract
The present invention provides a kind of method for preparing deuterated aminated compounds, using microwave device in the presence of deuterium source, deuterated aminated compounds is converted by the non-deuterated aminated compounds of the structure at least containing a formula C-N-X, wherein X is nitroso, nitro, cyano or halogen.Raw material of the invention easily obtains, and price is low, and dosage is few, easy to operate, and the deuterated time is short, and deuterated rate is high, and deuterated process is environmentally protective, is suitably applied the deuterated amine drug of exploitation.
Description
Technical field
The present invention relates to the field of chemical synthesis, and in particular to a kind of to prepare deuterated aminated compounds using microwave reaction device
Method.
Background technique
Deuterium isotope and its deuterated aminated compounds are widely applied in numerous research fields.Deuterated aminated compounds is not only
It may be used as the internal standard of clinical medicine analysis, for studying pharmacokinetics, drug-metabolic pathway and drug toxicology, it can be with
It is developed as better drug.
But the synthetic method of deuterated aminated compounds is there are still some disadvantages at present, as synthetic route is cumbersome, deuterated original
Material is expensive；Deuterated go back original reagent market shortage, price is high, is not easy to obtain；Metallic catalyst is expensive, deuterated rate is difficult to reach and want
It asks, to limit the application of deuterated aminated compounds.Therefore, it is necessary to develop, one kind is at low cost, it is simple and easy-operating to prepare
Deuterated aminated compounds preparation method.
Microwave technology is applied to organic synthesis, reaction speed accelerate than conventional method it is tens of or even thousands of times, and
And the substance that conventional method is difficult to generate can be synthesized, it is just more and more extensive to apply to material, pharmacy, chemical industry and other related sections
It grinds and teaching field.The non-deuterated aminated compounds of the structure at least containing a formula C-N-X is turned by microwave reaction device
The method for turning to deuterated aminated compounds has not been reported.
Summary of the invention
The present invention provides a kind of preparation method of deuterated aminated compounds, and the method is at least to contain a formula C-N-X
The non-deuterated aminated compounds of structure is raw material, under the reaction condition in deuterium source, alkali and microwave reaction device, in organic solvent
It is reacted to obtain deuterated aminated compounds.
Wherein, in the non-deuterated aminated compounds of the structure at least containing a formula C-N-X C atom at least with one
A hydrogen atom connection, N atom are not connect with hydrogen atom.
The reaction temperature is 50 degree of -200 degree under microwave condition, preferably 80 degree -150 degree；Most preferably 100 degree -120
Degree.
Wherein microwave frequency used in the microwave reaction device (Biotage, initiator EXP) is 50Hz-
2450MHz, power bracket 0-400W.
The deuterium source is selected from one or more of heavy water or the deuterated alcohol of C1-C4, preferably heavy water, deuterated ethyl alcohol
(d1), deuterated methanol (d1), deuterated methanol (d4), one or more of, most preferably heavy water, deuterated ethyl alcohol (d1), deuterated
Methanol (d1), the mixed solvent of heavy water and deuterated ethyl alcohol (d1), the mixed solvent of heavy water and deuterated methanol (d1) or heavy water with
The mixed solvent of deuterated methanol (d4).
The dosage in the deuterium source are as follows: 0.1mL-100mL deuterium source is added in every 1mmol substrate.
The alkali includes but is not limited to the sodium alkoxide of C1-C4, the potassium alcoholate of C1-C4, sodium carbonate, potassium carbonate, cesium carbonate, carbonic acid
The one or more of lithium, deuterium sodium oxide molybdena, deuterium potassium oxide, tert-butyl alcohol lithium or deuterate sodium, preferably sodium carbonate, potassium carbonate, cesium carbonate,
Lithium carbonate, deuterium sodium oxide molybdena, deuterium potassium oxide, sodium methoxide, sodium ethoxide, tert-butyl alcohol lithium, potassium tert-butoxide, sodium tert-butoxide or deuterate sodium one
Kind is several.
The wherein dosage of the alkali are as follows: 0.01mmol-10mmol alkali is added in every 1mmol substrate.
Wherein the reaction can according to need selection suitable reaction time, can be it is primary deuterated or repeatedly deuterated,
The primary deuterated reaction time can be -5 hours 10 minutes, for example, can be 30 minutes, 1 hour, 2 hours, 3 hours, it is 4 small
When or 5 hours.
Wherein the multiple deuterated time can be with solvent as be also possible to it is different.,
Wherein the system of the reaction can also include one or more organic solvents without active hydrogen, such as tetrahydro furan
It mutters or dioxane.
The wherein reaction can be added phase transfer catalyst or surfactant, the phase transfer catalyst it is unrestricted
Property example include tetrabutyl activation ammonium or crown ether, the non-limitative example of the surfactant include lauryl sodium sulfate or
Cetyl trimethylammonium bromide.
In some embodiments of the present invention, the non-deuterated aminated compounds includes formulaStructural element,
It preferably include formulaStructural element, more preferably include formulaOrKnot
Structure element, most preferably comprises formulaOrStructural element.
In some embodiments of the present invention, the non-deuterated aminated compounds includes formulaStructure want
Element, and the N atom in the structural element is not in any one cyclic structure；Preferably, the formulaStructure want
Element is formulaOrStructural element；More preferably formula
OrStructural element.
In some embodiments of the present invention, the non-deuterated aminated compounds contains at least two formula
Structural element；Preferably, at least there are two formulasStructural element in N atom in same cyclic structure；
It more preferably include formulaStructural element, wherein n=0-7 and m=0-4 or n=1 and m=1.
In some embodiments of the present invention, the non-deuterated aminated compounds includes formulaOrStructural element, wherein X be selected from C, N, O or
S, wherein n=0-7 and m=0-7；Preferably, when X elder generation is from C and n and m are 1, at least one carbon is former in the structural element
Son is connected with the group of non-hydrogen；More preferably when X is selected from C, n and m are not 1 simultaneously.
In some embodiments of the present invention, the non-deuterated aminated compounds includes formulaKnot
Structure element, wherein n=1-4；Preferably, as n=3, the group phase of at least one carbon atom and non-hydrogen in the structural element
Connection；It is highly preferred that n is not 3.
In some embodiments of the present invention, the formulaStructural element be formulaStructural element, preferably formulaOrStructural element, more preferably
For formulaStructural element, further preferably formulaStructural element most preferably contain
The structural elementCompound be
In some embodiments of the present invention, the non-deuterated aminated compounds includes formulaStructure
Element preferably comprisesStructural element, more preferably to include formulaOr's
Structural element further preferably includes formulaStructural element, most preferably include formula's
Structural element.
In some embodiments of the present invention, the non-deuterated aminated compounds includes formulaStructure
Element preferably includes formulaStructural element, more preferably includeStructural element, most preferably includeStructural element, wherein n=0-
4, m=0-4, j=0-4 and k=0-4, preferably n=0-1, m=0-1, j=0-1 and k=0-1.
In some more specific embodiments of the invention, the non-deuterated aminated compounds includes formulaStructural element, preferably include formulaOrKnot
Structure element more preferably includes formulaOrStructural element, further preferably wrap
ContainOrStructural element, most preferably include formulaStructural element.
In some embodiments of the present invention, the structural element of the formula C-N-X is formulaPreferably formulaStructural element；Specifically, the structure of the non-deuterated aminated compounds isIts
Middle R1, R2 and R3 be independently selected from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl,
Alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitroso, carboxyl and amino, wherein above-mentioned group
Optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, halogen
The lower alkoxy, rudimentary that naphthenic base that low alkyl group that element replaces, naphthenic base, halogen replace, lower alkoxy, halogen replace
Alkylthio group, mono- alkyl amino, di-alkyl amino, cycloalkyl amino and optionally by one or more halogens, hydroxyl, nitro, Asia
The aryl or heteroaryl that nitro, carboxyl, amino, low alkyl group, lower alkoxy, lower alkylthio replace；Or R1 and R2 phase
It connects and the ring of 3-12 member is collectively formed.Preferably, R1 and R3 is independently selected from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, ring
Alkyl, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitrous
Base, carboxyl and amino, and R2 is selected from alkyl；Wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen,
The cycloalkanes that hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, halogen replace
Lower alkoxy, the lower alkylthio, mono- alkyl amino, di-alkyl amino, naphthenic base that base, lower alkoxy, halogen replace
Amino and optionally by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, low
The aryl or heteroaryl that grade alkylthio group replaces；Or R1 and R2 is connected with each other the ring that 3-12 member is collectively formed.It is highly preferred that R1 and
R3 is independently selected from hydrogen, alkyl, phenyl, carboxyl, and R2 is selected from alkyl, and wherein alkyl is optional is taken by phenyl or carboxyl
Generation；Or R1 and R2 is connected with each other the ring that 3-12 member is collectively formed.
In some embodiments of the present invention, the structural element of the formula C-N-X is formulaStructure want
Element, preferably formulaStructural element；Specifically, the structure of the non-deuterated aminated compounds isWherein R4 and R5 is independently selected from from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, naphthenic base, heterocycle alkane
Base, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitroso, carboxyl and ammonia
Base, and R5 is not hydrogen；Wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, Asia
Nitro, carboxyl, amino, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, rudimentary alcoxyl
Lower alkoxy, lower alkylthio, mono- alkyl amino, di-alkyl amino, cycloalkyl amino and the optional quilt that base, halogen replace
One or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkylthio replace
Aryl or heteroaryl；Or R4 and R5 is connected with each other the ring that 3-12 member is collectively formed.Preferably, R4 is independent is selected from hydrogen, halogen
Element, alkyl, alkene hydrogen, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkane sulphur
Base, cyano, hydroxyl, nitro, nitroso, carboxyl and amino, and R5 is selected from alkyl；Wherein above-mentioned group is optionally by a kind of or more
Kind following substituent groups replace: low alkyl group that halogen, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, halogen replace,
Lower alkoxy, the lower alkylthio, mono- alkyl ammonia that naphthenic base, the naphthenic base of halogen substitution, lower alkoxy, halogen replace
Base, di-alkyl amino, cycloalkyl amino and optionally by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low
The aryl or heteroaryl that grade alkyl, lower alkoxy, lower alkylthio replace；Or 3-12 is collectively formed in R4 and R5 interconnection
The ring of member.It is highly preferred that R4 is selected from hydrogen, alkyl, phenyl, carboxyl, and R5 is selected from alkyl, wherein alkyl it is optional by phenyl or carboxylic
Base replaces；Or R4 and R5 is connected with each other the ring that 3-12 member is collectively formed.
In some embodiments of the present invention, the structural element of the formula C-N-X is formulaStructure want
Element, preferably formulaStructural element；Specifically, the structure of the non-deuterated aminated compounds isWherein R6, R7, R8, R9 and R10 are independently selected from from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, ring
Alkyl, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitrous
Base, carboxyl and amino, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, Asia
Nitro, carboxyl, amino, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, rudimentary alcoxyl
Lower alkoxy, lower alkylthio, mono- alkyl amino, di-alkyl amino, cycloalkyl amino and the optional quilt that base, halogen replace
One or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkylthio replace
Aryl or heteroaryl；Or R6 and R7 is connected with each other the ring that 3-12 member is collectively formed；Or R6 and R7 is connected with each other common shape
The ring that 3-12 member is collectively formed is connected with each other at the ring and R8 and R9 of 3-12 member.Preferably, R6, R7, R8, R9 and R10 be respectively
Independent to be selected from hydrogen, alkyl, phenyl and carboxyl, wherein alkyl is optional is replaced by phenyl or carboxyl；Or R6 with R7 phase interconnects
Connect the ring that 3-12 member is collectively formed.
In some specific embodiments of the invention, the structure of the non-deuterated aminated compounds isOrCorrespondingly, the structure for the deuterated aminated compounds being prepared isOr
In other embodiments of the invention, the structural element of the formula C-N-X is formulaStructure want
Element, preferably formulaStructural element；Specifically, the structure of the non-deuterated aminated compounds isWherein R11, R12, R13 and R14 are independently selected from from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, ring
Alkyl, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitrous
Base, carboxyl and amino, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, Asia
Nitro, carboxyl, amino, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, rudimentary alcoxyl
Lower alkoxy, lower alkylthio, mono- alkyl amino, di-alkyl amino, cycloalkyl amino and the optional quilt that base, halogen replace
One or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkylthio replace
Aryl or heteroaryl；Or R11 and R12 is connected with each other the ring that 3-12 member is collectively formed.Preferably, when R11 with R12 phase interconnects
It connects when 6 yuan of ring is collectively formed, is formed by ring and is at least replaced by a halogen, hydroxyl, nitro, nitroso, carboxyl or amino,
Or the cycloalkanes at least replaced by low alkyl group that substituted or unsubstituted low alkyl group, a halogen replace, naphthenic base, halogen
Lower alkoxy, the lower alkylthio, halogen that base, Heterocyclylalkyl, the Heterocyclylalkyl of halogen substitution, lower alkoxy, halogen replace
Lower alkylthio, mono- alkyl amino, di-alkyl amino or the cycloalkyl amino that element replaces replace；Or R11 with R12 phase interconnects
Connect the ring that 3-12 member is collectively formed.Preferably, R11, R12, R13 and R14 are independently selected from hydrogen, alkyl, phenyl and carboxyl,
Wherein alkyl is optional is replaced by phenyl or carboxyl；Or R11 and R12 is connected with each other the ring that 3-12 member is collectively formed.
In other embodiments of the invention, the structural element of the formula C-N-X is formulaStructure want
Element, preferably formulaStructural element；Specifically, the structure of the non-deuterated aminated compounds isWherein R15, R16 and R17 are independently selected from from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, cycloalkanes
Base, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitrous
Base, carboxyl and amino, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, Asia
Nitro, carboxyl, amino, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, rudimentary alcoxyl
Lower alkoxy, lower alkylthio, mono- alkyl amino, di-alkyl amino, cycloalkyl amino and the optional quilt that base, halogen replace
One or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkylthio replace
Aryl or heteroaryl；Or R15 and R16 is connected with each other the ring that 3-12 member is collectively formed.Preferably, R15, R16 and R17 be respectively
Independent to be selected from hydrogen, alkyl, phenyl and carboxyl, wherein alkyl is optional is replaced by phenyl or carboxyl；Or R15 and R16 is mutual
The ring of 3-7 member is collectively formed in connection.Preferably, when 6 member ring is collectively formed in R15 and R16 interconnection, it is formed by ring at least
Replaced by a halogen, hydroxyl, nitro, nitroso, carboxyl or amino, or at least by a substituted or unsubstituted lower alkyl
The Heterocyclylalkyl, low that naphthenic base that low alkyl group that base, halogen replace, naphthenic base, halogen replace, Heterocyclylalkyl, halogen replace
Lower alkylthio, the mono- alkyl amino, two-that grade alkoxy, the lower alkoxy of halogen substitution, lower alkylthio, halogen replace
Alkyl amino or cycloalkyl amino replace.
In other embodiments of the invention, the structural element of the formula C-N-X is formulaStructure want
Element, preferably formulaStructural element；Specifically, the structure of the non-deuterated aminated compounds isWherein R18 and R19 is independently selected from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, naphthenic base, heterocycle alkane
Base, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitroso, carboxyl and ammonia
Base, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, nitroso, carboxyl, ammonia
Base, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, lower alkoxy, halogen replace
Lower alkoxy, lower alkylthio, mono- alkyl amino, di-alkyl amino, cycloalkyl amino and optionally by one or more halogen
The aryl or heteroaryl that element, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkylthio replace
Base；Or R18 and R19 is connected with each other the ring that 3-12 member is collectively formed.Preferably, when R18 and R19 interconnection is collectively formed 6
When member ring, it is formed by ring and is at least replaced by a halogen, hydroxyl, nitro, nitroso, carboxyl or amino, or at least by one
A substituted or unsubstituted low alkyl group, halogen replace low alkyl group, naphthenic base, halogen replace naphthenic base, Heterocyclylalkyl,
Lower alkoxy, lower alkylthio, the halogen that Heterocyclylalkyl, lower alkoxy, the halogen of halogen substitution replace replace rudimentary
Alkylthio group, mono- alkyl amino, di-alkyl amino or cycloalkyl amino replace.Preferably, R18 and R19 are independently selected from
Hydrogen, alkyl, phenyl and carboxyl, wherein alkyl is optional is replaced by phenyl or carboxyl；Or R11 and R12 is connected with each other common shape
At the ring of 3-7 member.
In some specific embodiments of the invention, the structure of non-deuterated aminated compounds is OrCorrespondingly, the deuterated amine being prepared
The structure of class compound is Or
In other tool the present embodiment of the invention, the non-deuterated aminated compounds is
OrWherein in the structure, the connection type per two adjacent groups of Y1 to Y7 is
3-12 member is collectively formed in singly-bound connection or double bond connection, can also being connected with each other per two adjacent groups for the Y1 to Y7
Ring, such as formed substituted or unsubstituted phenyl ring；Preferably, it when 6 member ring is collectively formed in Y1-Y3 interconnection, is formed
Ring at least replaced by a halogen, hydroxyl, nitro, nitroso, carboxyl or amino, or it is at least substituted or unsubstituted by one
Low alkyl group, halogen replace low alkyl group, naphthenic base, halogen replace naphthenic base, Heterocyclylalkyl, halogen replace heterocycle
Lower alkylthio, the mono- alkyl that alkyl, lower alkoxy, the lower alkoxy of halogen substitution, lower alkylthio, halogen replace
Amino, di-alkyl amino or cycloalkyl amino replace.
Each group of Y1 to Y7 is independently selected from C (R23) (R24), N (R25), N (C (O) R26), NHC (O), C
(O), S (O) 2, C (O) O, OC (O), C (O) NH, N (N=O) or N (NO2), preferably C (R23) (R24), N (R25), O, S or N
(N=O), more preferably CH2, N (R25), O, S or N (N=O)；Wherein, R23 and R24 can be connected with each other and 3-12 is collectively formed
The ring of member, is preferably formed as the ring of 4-6 member.Wherein R20, R21, R22, R23, R24, R25 and R26 are independently selected from hydrogen, halogen
Element, alkyl, alkene hydrogen, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkane sulphur
Base, cyano, hydroxyl, nitro, nitroso, carboxyl and amino, wherein above-mentioned group is optionally by one or more following substituent groups
Replace: halogen, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, halogen
Lower alkoxy, the lower alkylthio, mono- alkyl amino, di-alkyl ammonia that substituted naphthenic base, lower alkoxy, halogen replace
Base, cycloalkyl amino and optionally by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, rudimentary
The aryl or heteroaryl that alkoxy, lower alkylthio replace.
In other specific embodiments of the invention, the structure of the non-deuterated aminated compounds isCorrespondingly, the deuterated aminated compounds being prepared isWherein n=0-
7；When n is 0, it is valence link, indicates three-membered ring；Specifically, the structure of non-deuterated aminated compounds isOrCorrespondingly, the deuterium being prepared
It is for aminated compoundsOr
In other specific embodiments of the invention, the structure of the non-deuterated aminated compounds isThe deuterated aminated compounds being prepared isWherein n=0-7 and m=
0-7, preferably n=1-7 and m=1-7, more preferably n=1 and m=1；X1 is selected from CH or N；Z1 is selected from hydrogen, halogen, alkyl, alkene
Hydrogen, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl
Base, nitro, nitroso, carboxyl and amino, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen,
The cycloalkanes that hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, halogen replace
Lower alkoxy, the lower alkylthio, mono- alkyl amino, di-alkyl amino, naphthenic base that base, lower alkoxy, halogen replace
Amino and optionally by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, low
The aryl or heteroaryl that grade alkylthio group replaces, it is preferable that when X1 is CH, m, n are not 1 simultaneously, and Z1 is not hydrogen；Preferably,
When X1 is N, Z1 is not nitroso, is not more preferably nitroso, nitro, hydroxyl, cyano or halogen, it is further preferred that working as
When X1 is N, Z1 is not H；Work as m, when n is 0 simultaneously, is valence link, indicates four-membered ring.
In other specific embodiments of the invention, the structure of the non-deuterated aminated compounds is
The deuterated aminated compounds being prepared isWherein X1 is selected from CH or N；A1, A2 or Z1 choosing independent
From hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl
Base, alkylthio group, cyano, hydroxyl, nitro, nitroso, carboxyl and amino, wherein above-mentioned group is optionally by one or more following
Substituent group replaces: low alkyl group, the cycloalkanes that halogen, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, halogen replace
Base, halogen replace naphthenic base, lower alkoxy, halogen replace lower alkoxy, lower alkylthio, mono- alkyl amino,
Di-alkyl amino, cycloalkyl amino and optionally by one or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, rudimentary
The aryl or heteroaryl that alkyl, lower alkoxy, lower alkylthio replace；Preferably, A1 and A2 is independently selected from hydrogen, Z1
Selected from ethyl, nitroso, phenyl, 6- nitro-pyridine -3- base, benzyl, N methyl piperazine -1- base, morpholine -1- base or 1H- pyrrole
- 1 base of azoles；Preferably, when X1 is CH, A1, A2, Z1 are not hydrogen simultaneously；It is highly preferred that Z1 is not nitroso when X1 is N,
It is preferred that not being nitroso, nitro, hydroxyl, cyano or halogen；It is further preferred that Z1 is not hydrogen when X1 is N.
It should be noted that when non-deuterated aminated compounds is converted into deuterated aminated compounds, on the group Z1
Hydrogen atom can partly or entirely be converted into D-atom, can also all be not converted into D-atom.
In other more specific embodiments of the invention, the structure of non-deuterated aminated compounds is
OrCorrespondingly, the structure for the deuterated aminated compounds being prepared is
Or
In other specific embodiments of the invention, the structure of the non-deuterated aminated compounds isCorrespondingly, the deuterated aminated compounds being prepared isWherein n=0-7
And m=0-7, preferably n=1-7 and m=1-7, more preferably n=1 and m=1；More preferably, when X1 is CH2, m+n ≠ 3.
Work as m, when n is 0 simultaneously, is valence link, indicates four-membered ring.
In some more specifical embodiments of the invention, the structure of the non-deuterated aminated compounds isOrCorrespondingly, the deuterated aminated compounds being prepared isOr
In some specific embodiments of the invention, the structure of the non-deuterated aminated compounds isThe deuterated aminated compounds being prepared isWherein n=1-7 and m=1-7,
Preferably n=1 and m=1；X1 and X2 is independently selected from CH or N；Z2 is selected from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, cycloalkanes
Base, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkoxy, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitrous
Base, carboxyl and amino, wherein above-mentioned group is optionally replaced by one or more following substituent groups: halogen, hydroxyl, nitro, Asia
Nitro, carboxyl, amino, low alkyl group, the low alkyl group of halogen substitution, naphthenic base, the naphthenic base of halogen substitution, rudimentary alcoxyl
Lower alkoxy, lower alkylthio, mono- alkyl amino, di-alkyl amino, cycloalkyl amino and the optional quilt that base, halogen replace
One or more halogens, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, lower alkoxy, lower alkylthio replace
Aryl or heteroaryl, preferably hydrogen.
In some specific embodiments of the invention, the structure of the non-deuterated aminated compounds isThe deuterated aminated compounds being prepared is accordinglyWherein n=0-7,
M=0-7, j=0-7 and K=0-7, preferably n=1-7, m=1-7, j=1-7 and K=1-7, more preferably n=1, m=1, j
=1 and k=1；Wherein X3 is selected from CH2, O, S or NH.
In some specific embodiments of the invention, the structure of the non-deuterated aminated compounds is
The deuterated aminated compounds being prepared isWherein n=0-7 and m=0-7, preferably n=0-1 and m=0-
1；As n=0 and m=0, it is valence link, indicates 6 member rings.
In still other more specifical embodiment of the invention, the structure of the non-deuterated aminated compounds isOrThe deuterated aminated compounds being prepared is accordinglyOr
In still other specific embodiment of the invention, the structure of the non-deuterated aminated compounds isThe deuterated aminated compounds being prepared isWherein n=0-7, m=0-7, j=0-7 and
K=0-7, preferably n=0-1, m=0-1, j=0-1 and K=0-1, more preferably n=0, m=0, j=1 and k=1；When m, n,
It is valence link when j or k is 0；Wherein X4 be hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substitution or
Unsubstituted alkynyl, substituted or unsubstituted naphthenic base, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl,
Substituted or unsubstituted heteroaryl；It is preferred that X4 is not hydrogen.
It should be noted that when non-deuterated aminated compounds is converted into deuterated aminated compounds, on the group X4
Hydrogen atom can partly or entirely be converted into D-atom, can also all be not converted into D-atom.
In some specific embodiments of the invention, the structure of the non-deuterated chemical combination is
OrThe deuterated amine chemical combination being prepared
Object is accordingly
Or
In some specific embodiments of the invention, the structure of the non-deuterated aminated compounds isSystem
It is for obtained deuterated aminated compoundsWherein n=0-7, m=0-7, j=0-7 and K=0-7, preferably n
=0-1, m=0-1, j=0-1 and K=0-1, more preferably n=1, m=1, j=0-1 and k=0-1；When m, n, j or k are 0,
For valence link；For example, the structure of the non-deuterated aminated compounds is
Or
When, the deuterated aminated compounds being prepared is accordingly
Or
In still other specific embodiment of the invention, the structure of the non-deuterated aminated compounds is
The deuterated aminated compounds being prepared isWherein n=1-7 and m=1-7, preferably n=1 and m=1.
In still other specific embodiment of the invention, the structure of the non-deuterated aminated compounds isThe deuterated aminated compounds being prepared isWherein n=0-7, preferably n=0-3；
It is valence link when n is 0.
In some specific embodiments of the invention, the structure of the non-deuterated aminated compounds isOrThe deuterated amine chemical combination being prepared
Object isOrWherein A3, A4, A5, A6, A7 and A8
It is independently selected from from hydrogen, halogen, alkyl, alkene hydrogen, alkynyl, naphthenic base, Heterocyclylalkyl, aryl, heteroaryl, alkoxy, alkane
Oxygroup, alkoxy carbonyl, alkylthio group, cyano, hydroxyl, nitro, nitroso, carboxyl and amino, wherein above-mentioned group optionally by
One or more following substituent groups replace: halogen, hydroxyl, nitro, nitroso, carboxyl, amino, low alkyl group, halogen replace
Low alkyl group, naphthenic base, halogen replace naphthenic base, lower alkoxy, halogen replace lower alkoxy, lower alkylthio,
Mono- alkyl amino, di-alkyl amino, cycloalkyl amino and optionally by one or more halogens, hydroxyl, nitro, nitroso, carboxylic
The aryl or heteroaryl that base, amino, low alkyl group, lower alkoxy, lower alkylthio replace；Preferably, A3, A4, A5, A6,
A7 and A8 are independently selected from hydrogen.
In still other more specific embodiment of the invention, the structure of the non-deuterated aminated compounds isOrCorrespondingly, the structure for the deuterated aminated compounds being prepared isOr
Beneficial effects of the present invention: it due to the unique heating method of microwave, can greatly improve in the reaction chemical anti-
Speed is answered, the activation energy of reaction is reduced, changes kinetics.Using the unique heating method of microwave and microwave to chemistry
There is " non-thermal effect " in reaction, can accelerate the progress of reaction, show its be swift in response, completely, yield is high, selectivity is good etc.
Advantage.The present invention prepares deuterated aminated compounds using microwave device, and deuterium source used is heavy water or deuterated alcohol, and deuterium source is easy to get,
And price is lower, easy preparation easy to operate, it, can be deuterated by most of raw material using microwave technology without adding metallic catalyst
Reaction time of the rate greater than 90% or more shortens to less than or equal to 5 hours, more efficiently, the deuterated process and subsequent transformation
The reagent that process does not use toxicity big, it is environmentally protective, particularly suitable for developing deuterated drug, make large-scale industry metaplasia
Deuterated drug is produced to be possibly realized.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
Specific embodiment
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
The reagents and materials used in the present invention are commercially available or can prepare by literature method.Tool is not specified in the following example
The experimental method of concrete conditions in the establishment of a specific crime, usually according to normal condition, or according to the normal condition proposed by manufacturer.Agents useful for same in embodiment
It is that commercially available analysis is pure.
Embodiment 1:
Reaction step: by compound 1, deuterium source, alkali, after mixing in microwave reactor (Biotage, initiator
EXP in), heating is reacted, and reaction is detected by mass spectrum, after having reacted, is extracted with dichloromethane three times, is merged organic
Phase is washed once with saturated sodium chloride solution, and anhydrous sodium sulfate is dry, is then spin-dried for obtaining compound 1D.Reaction is monitored with mass spectrum
Process, hydrogen deuterium exchange rate and the content D4=d4/ of d4 are judged according to the relative abundance of compound 1D (d1, d2, d3, d4)
1+d1+d2+d3+d4。
Table one: influence of the reaction condition to hydrogen deuterium exchange rate
Embodiment 2:
Reaction step: by compound 2, deuterium source, alkali is warming up to 80 degree and carries out instead after mixing in microwave reactor
It answers, as a result as shown in the table.The dissolubility in heavy water of compound 2 is poor, preferentially selects mixed solution.
Table two: reaction condition influences the rate that hydrogen deuterium exchanges
Table three: remaining embodiment compound reacts total time and twice deuterated rate
The above-mentioned obtained deuterated aminated compounds of experiment, can be further converted into the hydrochloride of deuterated amine or deuterated amine.
From the results, it was seen that the reaction time of the deuterated aminated compounds reacted under microwave condition is obviously shortened, twice
Deuterated rate is all larger than 95%, and deuterated rate significantly improves.
It is discussed in detail although the contents of the present invention have passed through above preferred embodiment, but it should be appreciated that above-mentioned
Description is not considered as limitation of the present invention.After those skilled in the art have read above content, for of the invention
A variety of modifications and substitutions all will be apparent.Therefore, protection scope of the present invention should be limited to the appended claims.
Claims (10)
1. a kind of preparation method of deuterated aminated compounds, which is characterized in that the method includes at least to contain a formula C-
The non-deuterated aminated compounds of N-X structure is raw material, under the reaction condition in deuterium source, alkali and microwave reaction device, organic molten
It is reacted to obtain deuterated aminated compounds in agent.
2. preparation method as described in claim 1, which is characterized in that the structure at least containing a formula C-N-X it is non-
C atom is at least connect with a hydrogen atom in deuterated aminated compounds, and N atom is not connect with hydrogen atom.
3. preparation method as described in claim 1, which is characterized in that the reaction temperature is 50 degree -200 under microwave condition
Degree.
4. preparation method as described in claim 1, which is characterized in that microwave frequency used in the microwave reaction device
For 50Hz-2450MHz, power bracket 0-400W.
5. preparation method as described in claim 1, which is characterized in that in deuterated alcohol of the deuterium source selected from heavy water or C1-C4
One or more.
6. preparation method as claimed in claim 5, which is characterized in that the deuterium source is selected from heavy water, deuterated ethyl alcohol (d1), deuterated
One or more of methanol (d1), deuterated methanol (d4), or/and, the mixed solvent of heavy water and deuterated ethyl alcohol (d1), heavy water with
One or more of mixed solvent, heavy water and mixed solvent of deuterated methanol (d4) of deuterated methanol (d1).
7. preparation method as described in claim 1, which is characterized in that the wherein dosage in the deuterium source are as follows: every 1mmol substrate
0.1mL-100mL deuterium source is added.
8. preparation method as described in claim 1, which is characterized in that the alkali includes but is not limited to the sodium alkoxide of C1-C4, C1-
One kind of the potassium alcoholate of C4, sodium carbonate, potassium carbonate, cesium carbonate, lithium carbonate, deuterium sodium oxide molybdena, deuterium potassium oxide, tert-butyl alcohol lithium or deuterate sodium
Or it is several.
9. preparation method as described in claim 1, which is characterized in that the wherein dosage of the alkali are as follows: every 1mmol substrate adds
Enter 0.01mmol-10mmol alkali.
10. preparation method as described in claim 1, which is characterized in that wherein the organic solvent be it is one or more not
Organic solvent containing active hydrogen.
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| CN103702961A (en) * | 2011-05-23 | 2014-04-02 | 赛诺菲 | Process for the preparation of deuterated compounds containing n-alkyl groups |
| WO2017045648A1 (en) * | 2015-09-18 | 2017-03-23 | 正大天晴药业集团股份有限公司 | Preparation method for deuterated compound |
| CN106565600A (en) * | 2016-10-28 | 2017-04-19 | 湖南大学 | Deuterated aza aromatic compound and synthesis method thereof |
| CN106892790A (en) * | 2017-03-16 | 2017-06-27 | 南京工业大学 | Method for preparing deuterated aniline compound by using microchannel reaction device |
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2017
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103702961A (en) * | 2011-05-23 | 2014-04-02 | 赛诺菲 | Process for the preparation of deuterated compounds containing n-alkyl groups |
| WO2017045648A1 (en) * | 2015-09-18 | 2017-03-23 | 正大天晴药业集团股份有限公司 | Preparation method for deuterated compound |
| CN106565600A (en) * | 2016-10-28 | 2017-04-19 | 湖南大学 | Deuterated aza aromatic compound and synthesis method thereof |
| CN106892790A (en) * | 2017-03-16 | 2017-06-27 | 南京工业大学 | Method for preparing deuterated aniline compound by using microchannel reaction device |
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