CN109206357A - A kind of general formula compound and its preparation method and application of gliclazide intermediate - Google Patents
A kind of general formula compound and its preparation method and application of gliclazide intermediate Download PDFInfo
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- CN109206357A CN109206357A CN201710539729.XA CN201710539729A CN109206357A CN 109206357 A CN109206357 A CN 109206357A CN 201710539729 A CN201710539729 A CN 201710539729A CN 109206357 A CN109206357 A CN 109206357A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The present invention relates to medical synthesis fields, and in particular to a kind of general formula compound and its preparation method and application of gliclazide intermediate.The present invention provides one kind to have such as following formula I structural compounds,Wherein, R1、R2、R3It is identical or unequally be H or C1~C6Alkyl, n, m it is identical or unequally be 0~3 integer.Compound of formula I is obtained by II compound of formula through nitro reduction, decarboxylation protecting group, the cyclization reaction of random order, then obtains III compound of formula through catalytic hydrogenation reaction, and III compound of formula reacts to obtain another IV structure gliclazide intermediate of formula through carbonyl reduction,Wherein, R1、R2、R3It is identical or unequally be H or C1~C6Alkyl, n, m it is identical or unequally be 0~3 integer.
Description
Technical field
The present invention relates to medical synthesis fields, and in particular to a kind of general formula compound of gliclazide intermediate and its preparation
Methods and applications.
Background technique
Gliclazide (Gliclazide), alias " Ge Likenasa ", trade name " Diamicron " are second generation sulfonylureas
Oral hypoglycemic drug can be effectively reduced blood glucose and improve coagulation function, and morbidity is applied alone diet control invalid after being mainly used for adult
And light, the middle patients with type Ⅰ DM without Ketosis-prone, especially suitable for the Non-Insulin Dependent Diabetes Mellitus patient of various hypotypes, pair is made
With smaller.
The chemical name of gliclazide is N- ((hexahydro cyclopenta [c] pyrroles -2 (1H)-yl) carbamyl) -4- first
Base benzsulfamide, structural formula are as follows:
The most critical technique of gliclazide synthesis is gliclazide side chain N- amino-3-azabicyclo [3.3.0] octane
Synthesis.Come currently, the country generallys use the method reported in Japan Patent (publication number JP05065270 and JP06041073)
Produce gliclazide side chain.This method using Tetrahydrocyclopenta(c)pyrrole-1,3(2H,3aH)-dione be raw material by reduction, nitrosation and zinc powder reduction and etc.
To target product:
But in the production method, there is reduction difficulty in the step of Tetrahydrocyclopenta(c)pyrrole-1,3(2H,3aH)-dione is reduced to octahydro ring penta [c] pyrroles
The prices such as larger, used reducing agent lithium aluminium hydride reduction and alkali metal hydride costly, easily cause explosion, transport and
All there is the problems such as biggish danger in use, it is therefore desirable to which new method prepares octahydro ring penta [c] pyrroles.
Summary of the invention
In order to solve the above technical problems, the present invention provides a kind of general formula compound of gliclazide intermediate and its preparations
Methods and applications prepare [c] pyrroles of octahydro ring penta and its general formula compound by raw material of the intermediate, eliminate existing preparation work
Security risk in the presence of skill reduces the requirement to reaction condition, low cost, in high yield, is suitble to industrialized production.
The technique concrete scheme is as follows:
The present invention provides a kind of compounds with such as following formula I structure:
Wherein, R1、R2、R3It is identical or unequally be H or C1~C6Alkyl, n, m are identical or are unequally 0~3
Integer；
That is, the Formulas I structural compounds can be with are as follows:
Wherein, R1、R2、R3、R4、R5、R6、R7It is identical or unequally be H or C1-C6Alkyl, n, m are identical or not identical
The integer that ground is 0~3；
Preferably, the Formulas I structural compounds are as follows:
Wherein, R1、R2、R3It is identical or unequally be H or C1~C6Alkyl；
Most preferably, the Formulas I structural compounds are as follows:
The present invention provides a kind of Formulas I ' preparation methods of structural compounds, the Formulas I ' structural compounds can be by such as following formula
Reduction, decarboxylation protecting group, cyclization reaction of II structural compounds through random order are prepared.
Reaction equation is as follows:
Wherein, R1、R2、R3It is identical or unequally be H or C1-C6Alkyl, R is carboxyl-protecting group, and n, m be identical or not phase
It together is 0~3 integer, it is describedIndicate bonding or non-bonding,
The R is preferably C1-C6Alkyl, benzyl, to methoxy-benzyl, to nitrobenzyl, hydrogen, more preferably C1-C6
Alkyl, most preferably ethyl；
The i.e. described reaction equation can be with are as follows:
Wherein, R1、R2、R3、R4、R5、R6、R7It is identical or unequally be H or C1-C6Alkyl, R is defined as above, n, m
Integer that is identical or being unequally 0~3, it is describedIndicate bonding or non-bonding；
It is highly preferred that it is above-mentioned the preparation method comprises the following steps:
R、R1、R2、R3It is defined as above, it is describedIndicate bonding or non-bonding；
Most preferably, above-mentioned the preparation method comprises the following steps:
R is defined as above, describedIndicate bonding or non-bonding；
It is described according to above-mentioned preparation methodIndicate bonding or non-bonding,Indicate that bonding up-to-date style I ' compound is formula
Compound I,Indicate that Formulas I ' compound is III compound of formula when not bonding；
According to above-mentioned preparation method, III compound of formula (Indicate that Formulas I ' compound is III chemical combination of formula when not bonding
Object) it is by II compound of formula through the nitro reduction of random order, decarboxylation protecting group, the preparation-obtained Formulas I of cyclization reaction
Conjunction object (Indicate that bonding up-to-date style I ' compound is compound of formula I) it is prepared again through catalytic hydrogenation reaction；
According to above-mentioned preparation method, the reaction dissolvent can be alcohols, alcohols/water, alkylbenzene, benzene, it is therefore preferable to first
Alcohol, ethyl alcohol, isopropanol, n-butanol, toluene, ethylbenzene, benzene, methanol/water, ethanol/water, isopropanol/water, n-butanol/water, more preferably
Ground is toluene, benzene, methanol, ethyl alcohol, isopropanol, most preferably isopropanol；
According to above-mentioned reduction reaction, the reagent that nitro is restored used in the reduction reaction is Fe/AcOH, Fe/HCl, Zn/
HCl、Sn/HCl、Pd/H2、Pt/H2、Ni/H2、PtO2/H2、Pd-C/H2Or Pd (OH)2/H2, reduction used in the reduction reaction
The reagent of carbon-carbon double bond is Pd/H2、Pt/H2、Ni/H2、PtO2/H2、Pd-C/H2Or Pd (OH)2/H2；
Preferably, the reagent that nitro is restored used in the reduction reaction is Fe/AcOH, Fe/HCl, Zn/HCl, Sn/
HCl、Pd/H2、Pd-C/H2、Pt/H2、Ni/H2、PtO2/H2Or Pd (OH)2/H2, reduction carbon-carbon double bond used in the reduction reaction
Reagent be Pd/H2, palladium carbon/H2、Pt/H2, Raney Ni/H2, platinum oxide/H2Or Pd (OH)/H2；
It is highly preferred that the reagent for restoring nitro used in the reduction reaction is Fe/AcOH, Fe/HCl, Pd/H2, described
The reagent that carbon-carbon double bond is restored used in reduction reaction is palladium carbon/H2, platinum oxide/H2, Raney Ni/H2；
Most preferably, the reagent of nitro is restored used in the reduction reaction for Fe/HCl, used in the reduction reaction
The reagent for restoring carbon-carbon double bond is palladium carbon/H2。
Above-mentioned decarboxylation protection group reaction can be acidolysis reaction or reduction reaction, it is therefore preferable to acidolysis reaction；
According to above-mentioned acidolysis reaction, the acid can be AcOH or HCl；
According to above-mentioned reduction reaction, the go back original reagent is identical as nitro go back original reagent.
Further, the present invention also provides a kind of application of Formulas I structural compounds, the formula that above-mentioned reaction is prepared
III structural compounds further can react to obtain such as IV structural compounds of following formula through carbonyl reduction.Reaction equation is as follows:
Wherein, R1、R2、R3It is identical or unequally be H or C1-C6Alkyl, n, m it is identical or unequally for 0~3 it is whole
Number；
That is, above-mentioned preparation method can be with are as follows:
Wherein, R1、R2、R3、R4、R5、R6、R7It is identical or unequally be H or C1-C6Alkyl, n, m are identical or not identical
The integer that ground is 0~3；
It is highly preferred that it is above-mentioned the preparation method comprises the following steps:
R、R1、R2、R3It is defined as above, it is describedIndicate bonding or non-bonding；
Most preferably, above-mentioned the preparation method comprises the following steps:
It is reacted according to above-mentioned carbonyl reduction, the reaction dissolvent is most preferably tetrahydrofuran；
It is reacted according to above-mentioned carbonyl reduction, the go back original reagent can be tri-butyl tin hydride, triphenyl tin hydride, three second
It is base silane, silicochloroform, tetra lithium aluminium hydride, sodium borohydride, sodium trimethoxy borohydride, 3-sec-butyl lithium borohydride, three secondary
Butyl potassium borohydride, lithium triethylborohydride, diisobutyl aluminium hydride, dihydro bis- (2- methoxy ethoxy) sodium aluminates, borine-
Tetrahydrofuran compound, more preferably tetra lithium aluminium hydride, borine-tetrahydrofuran compound, most preferably borine-tetrahydro furan
It mutters compound.
The general formula compound of gliclazide intermediate provided by the invention is used to prepare [c] pyrroles of octahydro ring penta and its leads to
Formula compound has the beneficial effect that the security risk eliminated in the presence of existing preparation process, reduces to reaction item
The requirement of part, and low cost, high yield.Therefore, gliclazide intermediate provided by the invention, have very high industrial application and
Economic value.
Specific embodiment
Content in order to better understand the present invention, combined with specific embodiments below to a kind of Ge Lieqi provided by the invention
The general formula compound and its preparation method and application of special intermediate is described in detail.It is to be appreciated that these embodiments are retouched
It states only as the feature that present invention be described in more detail, rather than to the limit of the scope of the invention or scope of the invention as claimed
System.
Embodiment 1: the preparation of compound of formula I
Into 500mL single-necked flask, addition II compound of formula (1.0g, 5.0mmol), isopropanol (50mL), 1M hydrochloric acid are water-soluble
Liquid (50mL)；At room temperature, nitrogen protection puts into iron powder (4.2g, 75mmol) in batches；It feeds intake and finishes, be vigorously stirred, TLC prison
It surveys and reacts, after about 3h, reaction is substantially completely.10% sodium hydrate aqueous solution is added dropwise, the pH value for adjusting solution is 8 or so, room temperature
Stir 1h.Diatomite filtering, filtrate are extracted with ethyl acetate (50mL x 3), merge organic phase, saturated salt solution (100mL)
It washes, anhydrous magnesium sulfate is dry, and solvent is removed under reduced pressure, obtains light yellow solid, is recrystallized, is obtained using ethyl acetate and n-hexane
Compound of formula I (0.55g, yield 88.7%) as white solid.
1H NMR(400MHz,CDCl3): δ 7.47 (bs, 1H), 3.91 (s, 2H), 2.56-2.34 (m, 6H) ppm.
13C NMR(100MHz,CDCl3):δ172.7,165.2,142.2,45.7,29.4,28.1,25.2ppm.
HRMS(ESI),[M+H]+calcd for C7H10NO 124.0757；found 124.0761.[M+Na]+calcd
for C7H9NNaO146.0576；found 146.0581.
Embodiment 2: the preparation of III compound of formula
Compound of formula I (3.8g, 30.9mmol), anhydrous methanol (30mL), (5%) are put into high-pressure hydrogenation kettle
Pd/C (1.1g), replaces high-purity H2After three times, it is filled with 2MPa H2, reaction 16h is stirred at room temperature.H is bled off in draught cupboard2, TLC inspection
Fully reacting is surveyed, diatomite filters out palladium carbon, and methanol (30mL) washs filter residue three times, and merging filtrate is concentrated under reduced pressure, obtains conduct
III compound of formula (3.55g, yield 92%) of white solid.
1H NMR(400MHz,CDCl3) δ 6.41 (s, 1H), 3.63-3.58 (m, 1H), 3.02 (d, J=7.2Hz, 1H),
2.84-2.82(m,2H),2.01-1.79(m,4H),1.68-1.52(m,4H)ppm.
HRMS(ESI),[M+H]+calcd for C7H12NO 126.0913；found 126.0918.[M+Na]+calcd
for C7H11NNaO148.0733；found 148.0735.
Embodiment 3: the preparation of III compound of formula
II compound of throw-in type (0.5g, 2.51mmol), isopropanol (10mL), Raney Ni into high-pressure hydrogenation kettle
(A-7063) (0.5g) and 10%NaOH aqueous solution (4mL), replace high-purity H2After three times, it is filled with 2.0MPa H2, room temperature stirs
Mix reaction 16h.H is bled off in draught cupboard2, TLC detects fully reacting, and diatomite filters out Raney Ni, ethyl acetate (10mL X
3) three times, merging filtrate is concentrated under reduced pressure, obtains formula III compound (0.21g, the yield as faint yellow solid washing filter residue
65%).
1H NMR(400MHz,CDCl3) δ 6.35 (brs, 1H), 3.62-3.58 (m, 1H), 3.02 (d, J=7.2Hz, 1H),
2.84-2.82(m,2H),2.01-1.81(m,4H),1.68-1.61(m,4H)ppm.
HRMS(ESI),[M+H]+calcd for C7H12NO 126.0913；found 126.0903.[M+Na]+calcd
for C7H11NNaO148.0733；found 148.0720.
Embodiment 4: the preparation of IV compound of formula
III compound of formula (1.25g, 10.0mmol) is added into 100mL three-necked flask, tetrahydrofuran (20mL) replaces nitrogen
Three times, ice-water bath is cooled to 0-5 DEG C to gas, and 1M BH is added dropwise3THF (20mL), is added dropwise, removes ice bath, is warmed to room temperature stirring
React 1h.It is placed in oil bath and is warming up to reflux, be stirred to react 3h.Heating is removed, restores to room temperature, methanol (10mL) is carefully added dropwise and quenches
It goes out reaction, solvent is removed under reduced pressure, be added methyl tertiary butyl ether(MTBE) (50mL), 3M aqueous hydrochloric acid solution (15mL) is heated to reflux 1h, stops
Heating, is cooled to room temperature to solution, and unsaturated carbonate aqueous solutions of potassium is added dropwise, and the pH value for adjusting solution is 9 or so, ethyl acetate extraction
(30mL x 3) merges organic phase, and saturated salt solution (50mL) is washed, and anhydrous magnesium sulfate is dry, and suction filtration is spin-dried for obtaining as white
IV compound of formula (0.89g, yield 80.3%) of solid.
1H NMR (400MHz, MeOD): δ 3.49 (s, 1H), 3.23 (s, 1H), 2.76-2.74 (m, 4H), 1.77-1.57
(m,6H)ppm.
HRMS(ESI),[M+H]+calcd for C7H15N 112.1121；found 112.1125.
The above description of the embodiment is only used to help understand the method for the present invention and its core ideas.It should be pointed out that pair
For those skilled in the art, without departing from the principle of the present invention, the present invention can also be carried out
Some improvements and modifications, these improvement and modification also fall in the protection scope of the claims in the present invention.
Claims (10)
1. a kind of compound with such as following formula I structure,
Wherein, R1、R2、R3It is identical or unequally be H or C1~C6Alkyl, n, m it is identical or unequally be 0~3 integer.
2. compound of formula I according to claim 1, which is characterized in that the structure of the compound of formula I are as follows:
Wherein, R1、R2、R3It is identical or unequally be H or C1~C6Alkyl.
3. compound of formula I according to claim 2, which is characterized in that the structure of the compound of formula I are as follows:
4. a kind of preparation method of Formulas I ' compound, which is characterized in that II compound of the Formulas I ' formula is through any
Reduction, decarboxylation protecting group, the cyclization reaction of sequence are prepared, reaction equation are as follows:
Wherein, R C1-C6Alkyl, benzyl, to methoxy-benzyl, to nitrobenzyl, hydrogen, R1、R2、R3It is identical or unequally be H
Or C1-C6Alkyl, n, m it is identical or unequally be 0~3 integer, it is describedIndicate bonding or non-bonding.
5. the preparation method according to claim 4, which is characterized in that II compound of the Formulas I ' formula is through appointing
Reduction, decarboxylation protecting group, the cyclization reaction of meaning sequence are prepared, reaction equation are as follows:
Wherein, R C1-C6Alkyl, benzyl, to methoxy-benzyl, to nitrobenzyl, hydrogen, R1、R2、R3It is identical or unequally be H
Or C1-C6Alkyl, it is describedIndicate bonding or non-bonding.
6. preparation method according to claim 5, which is characterized in that II compound of the Formulas I ' formula is through appointing
Reduction, decarboxylation protecting group, the cyclization reaction of meaning sequence are prepared, reaction equation are as follows:
Wherein, R C1-C6Alkyl, benzyl, to methoxy-benzyl, to nitrobenzyl, hydrogen, it is describedIndicate bonding or non-bonding.
7. according to preparation method described in claim 4,5 or 6, which is characterized in that the reaction dissolvent be alcohols, alcohols/water,
Alkylbenzene or benzene.
8. according to preparation method described in claim 4,5 or 6, which is characterized in that reduction nitro used in the reduction reaction
Reagent be Fe/AcOH, Fe/HCl, Zn/HCl, Sn/HCl, Pd/H2、Pt/H2、Ni/H2、PtO2/H2、Pd-C/H2Or Pd
(OH)2/H2, the reagent of reduction carbon-carbon double bond used in the reduction reaction is Pd/H2、Pt/H2、Ni/H2、PtO2/H2、Pd-C/H2
Or Pd (OH)2/H2。
9. the application of compound of formula I described in claim 1, which is characterized in that obtained by compound of formula I through catalytic hydrogenation reaction
III compound of formula, III compound of formula react to obtain the compound of IV structure of following formula through carbonyl reduction,
Wherein, n, m are identical or are unequally 0~3 integer.
10. application according to claim 9, which is characterized in that it is borine-that the carbonyl reduction, which reacts go back original reagent used,
Tetrahydrofuran compound, tetra lithium aluminium hydride, tri-butyl tin hydride, triphenyl tin hydride, triethylsilane, silicochloroform, boron
It is sodium hydride, sodium trimethoxy borohydride, 3-sec-butyl lithium borohydride, three sec-butyl potassium borohydrides, lithium triethylborohydride, two different
Butyl aluminum hydride or bis- (2- methoxy ethoxy) sodium aluminates of dihydro.
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2017
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