CN101838235B - 3-phenyl-3'-pyridylallylamine compound and synthesis method thereof - Google Patents
3-phenyl-3'-pyridylallylamine compound and synthesis method thereof Download PDFInfo
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- CN101838235B CN101838235B CN 200910086187 CN200910086187A CN101838235B CN 101838235 B CN101838235 B CN 101838235B CN 200910086187 CN200910086187 CN 200910086187 CN 200910086187 A CN200910086187 A CN 200910086187A CN 101838235 B CN101838235 B CN 101838235B
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Abstract
The invention discloses a method for preparing a compound show in a formula I, which is obtained by dehydrating the compound of a formula IV under t catalysis of inorganic acid or organic acid. The formula IV and the formula I are shown in the specification.
Description
Technical field:
The present invention relates to 3-phenyl-3 '-'-pyridylallylamine compound and synthetic method thereof.The invention still further relates to 3-phenyl-3 '-intermediate of '-pyridylallylamine compound.
Background technology:
3-phenyl-3 '-'-pyridylallylamine compound (formula I) is intermediate important in the pharmaceutical industry, as with ethyl propenoate Heck reaction, hydrolysis again, the medicine of the illnesss such as allergic rhinitis, spring fever, urticaria that can obtain medical treatment.
Formula I
Formula I compound (R
1Be selected from methyl, X halogen, R
2R
3Forming five-membered ring with N) warp reacts with ethyl propenoate Heck, hydrolysis obtains the medicine of illnesss such as a kind for the treatment of of allergic rhinitis, spring fever, urticaria again.The method of synthetic this kind medicine described in the patent EP0085959 is as follows:
In ether under-50 ℃ of conditions, 2,6-dibromo pyridine obtains intermediate 1 with the methylbenzene acetonitrile is reacted under the n-Butyl Lithium effect; Intermediate 1 obtains intermediate 2 with glycol reaction under the Catalyzed by p-Toluenesulfonic Acid in benzene; Intermediate 2 is obtaining intermediate 3 with the DMF reaction under-70 ℃ of conditions under the n-Butyl Lithium effect; Intermediate 3 in glycol dimethyl ether with phosphine acyl acetic acid three ethyl react intermediate 4; Phenol, glycol dibromide, triphenylphosphine and Pyrrolidine get side chain intermediate 5 through three-step reaction; Intermediate 4 and intermediate 5 in toluene, carry out under the n-Butyl Lithium effect Wittig react intermediate 6; Intermediate 6 is through sodium hydroxide hydrolysis, and the vitriol oil makes the transition, and the Virahol crystallization must this kind medicine.
This method has following shortcoming, is unsuitable for industrialization production:
1, raw material is not easy to obtain methylbenzene acetonitrile, phosphine acyl acetic acid three ethyl, causes the product cost height;
2, synthesis step is long, and 11 steps reaction, and condition harshness altogether is as needs low-temp reaction (70 ℃～-60 ℃);
3, aftertreatment difficulty, the chiral isomer separate complex causes yield low, and total recovery is less than 3%;
4, selected the explosive ether that is highly combustible for use in the reaction, the benzene that toxicity is very big, the glycol dibromide that environment is polluted;
5, because step is long, aftertreatment with the ether dilution, produces a large amount of waste liquids in a large number, is unfavorable for environmental protection.
Therefore, it is necessary that the selection raw material is easy to get, synthesizes easy compound I.
Summary of the invention:
The purpose of this invention is to provide formula I compound and synthetic method thereof.
Formula I compound provided by the invention and preparation method thereof is as follows:
Be raw material with formula IV compound, dehydration obtains target compounds of formula (I) under mineral acid or organic acid catalysis:
Formula IV formula I
Wherein,
R
1Be selected from hydrogen, halogen, hydroxyl, cyano group, C
1-4Acyloxy, C
1-4Alkoxyl group, C
1-4Alkyl and optional position the halogen alkyl, the C that replace
3-6Cycloalkyl;
R
2, R
3Be selected from identical or different hydrogen, C
1-4Alkyl or the 4-6 nitrogen heterocyclic that forms with nitrogen-atoms;
X is selected from halogen.
Above-mentioned formula IV compound is new compound, and its preparation method is as follows:
3) preparation formula II compound
With to alkylbenzene ethyl ketone, formaldehyde, amine, under the catalysis of mineral acid, carry out the Mannich reaction and obtain formula II, amine can select for use dialkyl group to replace secondary amine, and as Pyrrolidine, mineral acid can be selected hydrochloric acid for use.
Formula II
4) formula II and formula III react under lithiation reagent or grignard reagent catalysis and make formula IV compound, also can use the mixture of lithiation reagent and grignard reagent as catalyzer.
Described lithiation reagent is selected from n-Butyl Lithium or tert-butyl lithium, and magnesium reagent is selected from normal-butyl chlorination magnesium, normal-butyl bromination magnesium, isopropylmagnesium chloride, the sec.-propyl bromination magnesium one or both.
Wherein, the X in the formula III
1And X
2Identical or different, be selected from halogen respectively.
The present invention adopts brand-new synthetic technology, and synthesis step is short, is set out by the raw material p-methyl aceto phenone that is easy to get, and reaction can get key intermediate formula I compound (R through 3 steps
1Be selected from methyl, X halogen, R
2R
3Form five-membered ring with N), again through the reaction of 2 steps can this kind treatment of allergic rhinitis, the medicine of illnesss such as spring fever, urticaria, reduce by 6 steps than patent EP0085959 synthesis technique.In the reactions steps, owing to adopt this brand-new synthetic technology, in the synthetic compound of formula i process, reached dehydration effect transition simultaneously, the problem that does not have isomer separation in the subsequent reactions, in synthesis type IV compound process, adopt grignard reagent and tetrahydrofuran (THF), mild condition just can be synthesized under-5 ℃ of conditions, is beneficial to industrial production.Owing to reduced synthesis step, there is not the problem of isomer separation in the subsequent reactions, make total recovery bring up to 18%, lowered cost greatly.
Description of drawings:
Fig. 1 is embodiment 2 product 1-(6-bromo-2-pyridyl)-3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-alcohol
1The HNMR spectrum;
Fig. 2 is embodiment 3 product 2-bromo-6-(3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-thiazolinyl) pyridine
1The HNMR spectrum
Below by embodiment synthetic method of the present invention is described further, but the particular compound of enumerating among the embodiment do not limit the scope of the invention, adopt the method among the embodiment also can synthesize multiple substituent similar compound.
Embodiment
Pyrrolidine 123mL adds in the 2L reaction flask, transfers pH to acid with hydrochloric acid, adds 346.6ml 40% formalin, 200g p-methyl aceto phenone, 95 ℃ of backflow 10h.Solvent evaporated adds the acetone stirred crystallization, filters, and washing with acetone gets the hydrochloride of 3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-ketone, fusing point: 162～163 ℃.With back solvent extraction 3 times, wash NaSO in the filter cake usefulness alkaline solution
4Drying, recrystallization.Fusing point: 46～48 ℃, content＞98%, yield about 80%.(M
+1：218；IR(cm
-1)：V
C＝O：1680cm
-1，V
＝C-H：3022cm
-1，V
C＝C：1454cm
-1，1604cm
-1，V
CH3：2943cm
-1，V
C-CO-C：1207cm
-1，1228cm
-1；UV(nm)：253.6，222.2)
Under the nitrogen protection ,-5 ℃, sec.-propyl bromination magnesium/tetrahydrofuran (THF) (38.7mL/20mL) is added drop-wise to 2, in 6-dibromo pyridine/tetrahydrofuran (THF) (20g/100mL), below-5 ℃, reaction 1.5h, TLC monitoring reaction (sherwood oil: ethyl acetate=5: 1, Rf=0.62); Under-10 ℃, be added dropwise to 3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-ketone/tetrahydrofuran (THF) liquid (18.3g/50mL) ,-10 ℃～-5 ℃ reaction 3h, cancellation reaction.Water layer transfers pH to alkalescence with buck, extracts washing, MgSO
4Drying is filtered, concentrate to do, crystallization, dry 1-(6-bromo-2-pyridyl)-3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-alcohol, fusing point: 105～107 ℃, content＞98%, yield about 65%.(M
+ 1: 375;
1HNMR (500MHz, CDCl
3): δ (ppm) 1.89 (m, 4H), 2.32 (s, 3H), 2.60 (m, 2H), 2.72 (m, 6H), 7.11 (d, J=8.0Hz, 2H), 7.28 (m, 1H), 7.48 (m, 1H), 7.51 (2H), 7.65 (m 1H) (sees accompanying drawing 1) for d, J=8.0Hz; IR (cm
-1): V
O-H: 3431cm
-1, V
C-O: 1124cm
-1, V
C-Br: 565cm
-1, V
C=C: 1458cm
-1, 1546cm
-1, 1571cm
-1, 1629cm
-1, V
CH3: 2960cm
-1UV (nm): 270,245.5)
1The HNMR collection of illustrative plates is seen Fig. 1.
Under the nitrogen protection ,-30 ℃, in n-Butyl Lithium/tetrahydrofuran (THF) (38.7mL/20mL), drip 2,6-dichloropyridine/tetrahydrofuran (THF) (20g/100mL), below-30 ℃, reaction 1h, TLC monitoring reaction (sherwood oil: ethyl acetate=5: 1, Rf=0.51); Be added dropwise to 3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-ketone/tetrahydrofuran (THF) liquid (18.3g/50mL) at-30 ℃ ,-30 ℃～-20 ℃ reaction 3h, cancellation reaction.Stir evenly separatory, organic layer abandons, and water layer transfers pH to alkalescence with buck, extracts washing, MgSO
4Drying is filtered, concentrate to do, crystallization, dry 1-(6-chloro-2-pyridyl)-3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-alcohol, fusing point: 85～88 ℃, content＞97%, yield about 45%.(M
+1：331；
1HNMR(500MHz，CDCl
3)：δ(ppm)1.88(m，4H)，2.35(s，3H)，2.61(m，2H)，2.72(m，6H)，7.14(d，J＝8.0Hz，2H)，7.30(m，1H)，7.56(m，1H)，7.52(d，J＝8.0Hz，2H)，7.75(m，1H)；IR(cm
-1)：V
O-H：3512m
-1，V
C-O：1130cm
-1，V
C-Cl：662cm
-1，V
C＝C：1486cm
-1，1535cm
-1，1565cm
-1，1617cm
-1，V
CH3：2960cm
-1；UV(nm)：268，243)
In reactor, add the vitriol oil/water (100ml/18-22ml), intensification 60-80 ℃, add raw material 1-(6-bromo-2-pyridyl)-3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-alcohol (0.028mol), insulation 5-6h, HPLC detects.
Cool off 20-30 ℃ as early as possible, add water dilution after, be neutralized to PH 9-11 with buck immediately, with methylbenzene extraction 3 times, saturated brine washing 3 times, the MgSO4 drying, activated carbon decolorizing filters, 40 ℃ concentrate, obtain yellow oil.
Use dissolve with methanol, drip saturated oxalic acid/methanol solution, be 3-5 up to PH, produce a large amount of solids, about 20 ℃ of filtrations, obtaining yellow solid is the oxalate (content＞95%) of E-2-bromo-6-(3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-thiazolinyl) pyridine, fusing point: 172～174 ℃, and yield about 75%.(M
+ 1: 357;
1HNMR (500MHz, CDCl
3): δ (ppm) 1.91 (m, 4H), 2.42 (s, 3H), 2.80 (m, 4H), 3.40 (d, J=7.5Hz, 2H), 6.81 (d, J=7.5Hz, 1H), 7.10 (d, J=8.0Hz, 2H), 7.14 (t, J=7.0Hz, 1H), 7.25 (d, J=8.0Hz, 2H), 7.32 (m, 1H), 7.36 (m 1H) (sees accompanying drawing 2); IR (cm
-1): V
=C-H: 3100cm
-1, V
C-Br: 576cm
-1, V
C=C: 1421cm
-1, 1506cm
-1, 1550cm
-1, 1570cm
-1, V
CH3: 2960cm
-1UV (nm): 294,273.5,242,225.5)
The 1HNMR collection of illustrative plates is seen Fig. 2.
In reactor, add the vitriol oil/water (100ml/18-22ml), intensification 30-40 ℃, add raw material 1-(6-bromo-2-pyridyl)-3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-alcohol (0.028mol), insulation 2-3h, HPLC detects.
After adding water dilution, be neutralized to PH 9-11 with buck immediately, use methylbenzene extraction 3 times, saturated brine washing 3 times, the MgSO4 drying, activated carbon decolorizing filters, and concentrates below 40 ℃, obtains yellow oil.
Use dissolve with methanol, drip saturated oxalic acid/methanol solution, be 3-5 up to PH, produce a large amount of solids, about 20 ℃ of filtrations, obtaining yellow solid is the oxalate (content＞90%) of Z-2-bromo-6-(3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-thiazolinyl) pyridine, fusing point: 171～173 ℃, and yield about 80%.(M
+1：357；
1HNMR(500MHz，CDCl
3)：δ(ppm)1.91(m，4H)，2.42(s，3H)，2.80(m，4H)，3.40(d，J＝7.5Hz，2H)，6.39(d，J＝7.5Hz，1H)，7.10(d，J＝8.0Hz，2H)，7.14(t，J＝7.0Hz，1H)，7.25(d，J＝8.0Hz，2H)，7.32(m，1H)，7.36(m，1H)；IR(cm
-1)：V
＝C-H：3110cm
-1，V
C-Br：578cm
-1，V
C＝C：1422cm
-1，1507cm
-1，1550cm
-1，1570cm
-1，V
CH3：2960cm
-1；UV(nm)：294，273.5，242，225.5)
In reactor, add the vitriol oil/water (100ml/18-22ml), intensification 30-40 ℃, add raw material 1-(6-bromo-2-pyridyl)-3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-alcohol (0.028mol), insulation 2-3h, HPLC detects.
After adding water dilution, be neutralized to PH 9-11 with buck immediately, use methylbenzene extraction 3 times, saturated brine washing 3 times, the MgSO4 drying, activated carbon decolorizing filters, and concentrates below 40 ℃, obtains yellow oil.
Using dissolve with methanol, drip saturated oxalic acid/methanol solution, is 3-5 up to PH, produce a large amount of solids, about 20 ℃ of filtrations, obtaining yellow solid is the oxalate (content＞93%) of Z-2-chloro-6-(3-(1-pyrrolidyl)-1-(4-aminomethyl phenyl)-1-thiazolinyl) pyridine, fusing point: 148～151 ℃.(M
+1：357；
1HNMR(500MHz，CDCl
3)：δ(ppm)1.90(m，4H)，2.38(s，3H)，2.76(m，4H)，3.41(d，J＝7.5Hz，2H)，6.38(d，J＝7.5Hz，1H)，7.12(d，J＝8.0Hz，2H)，7.16(t，J＝7.0Hz，1H)，7.26(d，J＝8.0Hz，2H)，7.38(m，1H)，7.46(m，1H)；IR(cm
-1)：V
＝C-H：3112cm
-1，V
C-Cl：675cm
-1，V
C＝C：1442cm
-1，1509cm
-1，1550cm
-1，1575cm
-1，V
CH3：2962cm
-1；UV(nm)：292，271，240，223)
Claims (2)
1. the preparation method of formula I compound, step is as follows:
1) preparation formula II
Amine reacts under mineral acid catalysis shown in acetophenone derivs shown in the formula V, formaldehyde, the formula VI:
2) formula II and formula III react under grignard reagent catalysis, obtain formula IV:
3) formula IV compound dewaters under mineral acid or organic acid catalysis, obtains formula I:
Wherein, R
1Be selected from the alkyl of hydrogen, halogen, hydroxyl, cyano group, C1-4 acyloxy, C1-4 alkoxyl group, C1-4 and the alkyl that the optional position halogen replaces, the cycloalkyl of C3-6;
R
2, R
3Identical or different, be selected from the alkyl of hydrogen, C1-4 or the 4-6 nitrogen heterocyclic that forms with nitrogen-atoms respectively;
X is halogen;
X1 and X2 in the formula III are identical or different, are selected from halogen respectively.
2. the described method of claim 1, wherein amine described in the step 1) is two (C1-C4) alkyl secondary amine, mineral acid is hydrochloric acid; Step 2) grignard reagent described in is selected from one or both in normal-butyl chlorination magnesium, normal-butyl bromination magnesium, isopropylmagnesium chloride, the sec.-propyl bromination magnesium.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0085959A2 (en) * | 1982-02-04 | 1983-08-17 | The Wellcome Foundation Limited | Aromatic compounds |
| CN1148337A (en) * | 1994-02-08 | 1997-04-23 | Nps药物有限公司 | Compound active at a novel site on receptor-operated calcium channels usefull for treatment of neurological disorders and diseases |
| CN1192679A (en) * | 1995-06-07 | 1998-09-09 | Nps药物有限公司 | Compounds active at a novel side on receptor-operated calcium channel useful for treatment of neurological disorders |
-
2009
- 2009-06-12 CN CN 200910086187 patent/CN101838235B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0085959A2 (en) * | 1982-02-04 | 1983-08-17 | The Wellcome Foundation Limited | Aromatic compounds |
| CN1148337A (en) * | 1994-02-08 | 1997-04-23 | Nps药物有限公司 | Compound active at a novel site on receptor-operated calcium channels usefull for treatment of neurological disorders and diseases |
| CN1192679A (en) * | 1995-06-07 | 1998-09-09 | Nps药物有限公司 | Compounds active at a novel side on receptor-operated calcium channel useful for treatment of neurological disorders |
Non-Patent Citations (1)
| Title |
|---|
| Hon Wai Lam et al.Diastereoselective Synthesis of 4-Hydroxypiperidin-2-ones via Cu(I)-Catalyzed Reductive Aldol Cyclization.《ORGANIC LETTERS》.2005,第7卷(第25期),5743-5746,supporting information. * |
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