CN1371903A - Optical isomer of 3-methyl fentanyl, derivant, synthesizing and its analgesic activity - Google Patents
Optical isomer of 3-methyl fentanyl, derivant, synthesizing and its analgesic activity Download PDFInfo
- Publication number
- CN1371903A CN1371903A CN 01105491 CN01105491A CN1371903A CN 1371903 A CN1371903 A CN 1371903A CN 01105491 CN01105491 CN 01105491 CN 01105491 A CN01105491 A CN 01105491A CN 1371903 A CN1371903 A CN 1371903A
- Authority
- CN
- China
- Prior art keywords
- cis
- trans
- methyl
- methylfentanyl
- compound
- 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.)
- Granted
Links
- MLQRZXNZHAOCHQ-UHFFFAOYSA-N 3-methylfentanyl Chemical group C=1C=CC=CC=1N(C(=O)CC)C(C(C1)C)CCN1CCC1=CC=CC=C1 MLQRZXNZHAOCHQ-UHFFFAOYSA-N 0.000 title claims abstract description 20
- 230000003287 optical effect Effects 0.000 title claims description 24
- 230000000202 analgesic effect Effects 0.000 title description 16
- 241001597008 Nomeidae Species 0.000 title 1
- 230000002194 synthesizing effect Effects 0.000 title 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 147
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 28
- 238000006243 chemical reaction Methods 0.000 claims description 26
- 238000000034 method Methods 0.000 claims description 20
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 8
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 8
- 229910004013 NO 2 Inorganic materials 0.000 claims description 7
- -1 fluoro-ethylbromopropiophenone Chemical compound 0.000 claims description 6
- 239000000010 aprotic solvent Substances 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 4
- HQAXZGSXHOKGLA-UHFFFAOYSA-N 3-methyl-n-phenylpiperidin-4-amine Chemical compound CC1CNCCC1NC1=CC=CC=C1 HQAXZGSXHOKGLA-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 2
- 238000006482 condensation reaction Methods 0.000 claims 2
- 208000030507 AIDS Diseases 0.000 claims 1
- 229940124321 AIDS medicine Drugs 0.000 claims 1
- AWMVMTVKBNGEAK-UHFFFAOYSA-N Styrene oxide Chemical class C1OC1C1=CC=CC=C1 AWMVMTVKBNGEAK-UHFFFAOYSA-N 0.000 claims 1
- 229940035676 analgesics Drugs 0.000 claims 1
- 239000000730 antalgic agent Substances 0.000 claims 1
- 229940124599 anti-inflammatory drug Drugs 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 claims 1
- 229940041181 antineoplastic drug Drugs 0.000 claims 1
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 abstract description 26
- 229960005181 morphine Drugs 0.000 abstract description 13
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- 238000005160 1H NMR spectroscopy Methods 0.000 description 41
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- 238000004458 analytical method Methods 0.000 description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
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- ZTHRQJQJODGZHV-UHFFFAOYSA-N n-phenylpropanamide Chemical compound CCC(=O)NC1=CC=CC=C1 ZTHRQJQJODGZHV-UHFFFAOYSA-N 0.000 description 16
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
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- 230000036592 analgesia Effects 0.000 description 12
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 8
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- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- FRPRNNRJTCONEC-BVYCBKJFSA-N ohmefentanyl Chemical compound C1([C@H](O)CN2CC[C@@H]([C@@H](C2)C)N(C(=O)CC)C=2C=CC=CC=2)=CC=CC=C1 FRPRNNRJTCONEC-BVYCBKJFSA-N 0.000 description 6
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 5
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- 239000007864 aqueous solution Substances 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
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- 239000012141 concentrate Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- PJMPHNIQZUBGLI-UHFFFAOYSA-N fentanyl Chemical compound C=1C=CC=CC=1N(C(=O)CC)C(CC1)CCN1CCC1=CC=CC=C1 PJMPHNIQZUBGLI-UHFFFAOYSA-N 0.000 description 4
- 229960002428 fentanyl Drugs 0.000 description 4
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- 230000036407 pain Effects 0.000 description 4
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- 235000015320 potassium carbonate Nutrition 0.000 description 4
- 230000003389 potentiating effect Effects 0.000 description 4
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 4
- GBBSAMQTQCPOBF-UHFFFAOYSA-N 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane Chemical compound CB1OB(C)OB(C)O1 GBBSAMQTQCPOBF-UHFFFAOYSA-N 0.000 description 3
- YKLMHYUFNDAZAG-UHFFFAOYSA-N 2-chloro-1-(4-nitrophenyl)ethanone Chemical compound [O-][N+](=O)C1=CC=C(C(=O)CCl)C=C1 YKLMHYUFNDAZAG-UHFFFAOYSA-N 0.000 description 3
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- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 3
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- QARVLSVVCXYDNA-UHFFFAOYSA-N bromobenzene Chemical compound BrC1=CC=CC=C1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 3
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- ZUJVGRUIXVTXOX-QMMMGPOBSA-N (1r)-2-chloro-1-(4-nitrophenyl)ethanol Chemical compound ClC[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 ZUJVGRUIXVTXOX-QMMMGPOBSA-N 0.000 description 2
- ZJFWCELATJMDNO-UHFFFAOYSA-N 2-bromo-1-(4-fluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CBr)C=C1 ZJFWCELATJMDNO-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
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- NGJACAHAGMHHQT-LBPRGKRZSA-N methyl (2s)-1-benzylpyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1CC1=CC=CC=C1 NGJACAHAGMHHQT-LBPRGKRZSA-N 0.000 description 2
- LKRMTUUCKBQGFO-UHFFFAOYSA-N n-phenylpiperidin-4-amine Chemical class C1CNCCC1NC1=CC=CC=C1 LKRMTUUCKBQGFO-UHFFFAOYSA-N 0.000 description 2
- ALKIXOSJRUZYPH-UHFFFAOYSA-N n-phenylpropanamide;hydrochloride Chemical compound Cl.CCC(=O)NC1=CC=CC=C1 ALKIXOSJRUZYPH-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
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- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The present invention provides a stereo-isomer of 3-methyl fentanyl derivative. The pharmacological research shows that it possesses obvious pain-stopping activity, and its action time is long and its addition is low. Its pain-stopping effect is thousands times that of morphine.
Description
The present invention relates to the chemosynthesis of 3-methyl fentanyl derivative and their biological activity, the synthetic analgesic activity that reaches them of the 3-methyl fentanyl derivative optical isomer of more specifically saying so.
Fentanyl is that onset of pain control is fast, action time is short at the famous potent analgesia medicine of twentieth century discovery at the beginning of the sixties, and analgesia intensity is 200 times of morphine, now has been widely used in clinical.More deep structure of modification is found, the piperidine ring of fentanyl is introduced methyl and is got 3-methyl fentanyl, cis-(±)-3-methyl fentanyl analgesia usefulness has improved 6 times than fentanyl, 3-methyl fentanyl has two pairs of totally 4 optical isomers, their analgesia usefulness has very big stereo disparity, act on the strongest optical isomer cis-(+)-(3R, 4S)-3-methyl fentanyl analgesia usefulness is 2600 times of morphine; Introduce hydroxyl again in the β-position of the 1-of 3-methyl fentanyl styroyl and get ohmefentanyl, analgesic activities improves a lot again, ohmefentanyl has three pairs of totally 8 optical isomers, their analgesia usefulness also has very big stereo disparity, suitable-(+)-(3R, 4S, 2 ' S)-the analgesia usefulness of ohmefentanyl is unexpectedly up to 13000 times of morphine, is the μ-opioid receptor agonist that analgesic activity is the strongest, selectivity is best of generally acknowledging at present.
Fentanyl
3-methyl fentanyl
Ohmefentanyl
Allied compound synthetic prior art reflects J.Org.Chem 1995,38,3652-3659 in following document; Tetrahedron 1998,54,13059-13072; J.Am.Chem.Soc.1987,109,5551-5553; Chem.Int.Ed.1998,37,1986-2012.
The objective of the invention is 3-methyl fentanyl and ohmefentanyl are carried out chemically modified, adopt the optical isomer of the synthetic 3-methyl fentanyl derivative pharmacological screening that eases pain, seek out the compound that effect is good and side effect is little.
3-methyl fentanyl derivative of the present invention can be represented with following general formula (I):
Wherein, R
1=F, Cl, NO
2, NH
2Deng
R
2＝OH，＝O
R
3=H
The present invention implements through the following steps:
By benzyl piepridine ketone is raw material, through condensation, reduce, take off benzyl, fractionation and 3-methyl-four optical isomers of 4-anilino piperidines (II).Synthetic route is as follows:
(a)PhNH
2/toluene/acetic?acid；
(b)KBH
4/MeOH；
(c)10％Pd-C/H
2
(d)fractional?crystallization?of?fumarate?and?oxalate；
(e)tartaric?acid?resolution.
The rerum natura constant of table 1:3-methyl-four optical isomers of 4-anilino piperidines (II)
| Compound | Absolute configuration | Fusing point (℃) | [a] D 25(MeOH) |
| Cis-(+)-II | (3R，4S) | 97-98 | +7.25°(c0.66) |
| Cis-(-)-II | (3S，4R) | 96-98 | -7.67°(c0.32) |
| Trans-(+)-II | (3S，4S) | Light yellow oil | +112.91°(c0.86) |
| Trans-(-)-II | (3R，4R) | Light yellow oil | -110.82°(c1.0) |
The synthesized reference document (Zhi-Xian Wang, J.Med.Chem1995,38,3652～3659) of 3-methyl-4-anilino piperidines (II),
Right-nitrophenyl oxyethane (III, R=NO
2) synthesized reference document (the Zhi-Liang Wei of two optical isomers, Tetrahedron 1998,54,13059～13072 and Marcia deCarvalho, Tetrahedron 1991,47,2073～2080) with the active bacterium of geotrichum candidum and yeast selective reduction 2-chloro-4 '-nitro-acetophenone, cyclization prepares under alkaline condition then.
(f) the active bacterium G38/ of geotrichum candidum nutrient solution/r.t.18hr
(g) yeast/nutrient solution/r.t.30hr
(h)20％NaOH/r.t.
Right-chloro-phenyl-oxyethane (IV, R=Cl) the synthetic reference literature of two optical isomers (E.J.Corey, J.Am.Chem.Soc.1987,109,5551～5553 and C.J.Helal, Angew.Chem.Int.Ed.1998,37,1986～2012).
The applications catalyst selective reduction to 2,4 '-dichloroacetophenone, cyclization prepares under alkaline condition then.
Catalyzer is R-(+)-or S-(-)-tetrahydrochysene-1-methyl 3,3-phenylbenzene-1H, 3H-pyrrolo--[1; 2, c] [1,3; 2] oxazole borines (V) are by (R-)-or (S)-proline(Pro) is a raw material, through benzyl protection, esterification, grignard reaction, take off benzyl ring borineization and obtain.
(i)phCH
2Br/NaOH
(j)MeOH/H
+
(k)Mg/PhBr
(l)Pd-C/H
2
(m) trimethylboroxin
(n)S-(-)-V/THF.BH
3/THF
(o)R-(+)-V/THF.BH
3/THF
(h)20％NaOH/r.t.
Obtain to have optically active compound III or IV and have optically active II compound from aforesaid method and carry out condensation and must have optically active compound VI.
Compound VI is reacted to such an extent that have optically active compound VII with propionyl chloride or propionic anhydride in the presence of aprotic solvent such as chloroform, toluene, benzene, methylene dichloride, and compound VI I is at K
2CO
3Exist down aqueous methanol be solvent be hydrolyzed Ia, b, c compound.
Reaction formula is as follows:
R
1Be NO
2, Cl, F
Work as R
1Be NO
2The time, again through reduce I-b
Can be during reduction with using reductive agent, for example reduction such as palladium-carbon, Ranning nickel always.
The preparation of I-d compound
Right-fluoro-second bromobenzene acetone and optically active Compound I I reaction obtains I-d, again with propionyl chloride or propionic anhydride react compound VI I, K in the dilute methanol
2CO
3Exist hydrolysis down, fractional crystallization to get the I-e compound.
Biological activity determination:
1. analgesic activities is measured: two kinds of methods are measured
Method 1. woolfe-Macdonald methods [are seen Xu uncle Yun Dengbian: pharmacological experimental methodology (second edition), People's Health Publisher in November, 1991]: the female adult small white mouse of body weight 18～22g, be placed on the metal sheet that is preheated to 55 ℃, be pain indicator reaction commonly used to add metapedes, the pain reaction times prolonged the effective analgesic activity of person's conduct more than 1 times after subcutaneous injection awarded testing drug, calculated half mouse analgesia significant quantity ED with the FinneyShi method
50, be the analgesia strength ratio that benchmark calculates each isomer with the morphine.
Method 2. mouse anti acetate writhing methods: select 18～22 gram male mices for use, 10 every group, behind the subcutaneous administration 12 minutes, abdominal injection 1% acetate 10ml/kg, the embodiment of observing in 10～15 minutes turned round resembles.Complete antitorque body is positive.Calculate ED with the Bliss method
50Value.With the morphine is the analgesia strength ratio that benchmark calculates each isomer.
2. analgesic activity time:
Woolfe-Macdonald method: experiment condition is with analgesic activities measuring method 1, with ED
95Be dosage, measure the analgesic activity time.Experimental result sees the following form:
Table 1 I-a (R
1=NO
2, R
2/ R
3=OH/H) 8 steric isomer analgesic activities
*
| Compound | Absolute configuration | ????ED 50(μg/Kg) | Potent than (morphine=1) |
| ??I-a-a | ??cis-(-)-(3R，4S，2’R) | ????54.546(34.544-60.053) | ????14.8 |
| ??I-a-b | ??cis-(+)-(3R，4S，2’S) | ????23.624(21.366-26.119) | ????34.1 |
| ??I-a-c | ??cis-(-)-(3S，4R，2’R) | ????10.0mg/Kg(0/10) | ????- |
| ??I-a-d | ??cis-(+)-(3S，4R，2’S) | ????6609(4870-8967 | ????0.12 |
| ??I-a-e | ??trans-(+)-(3S，4S，2’S) | ????1052(775-1428) | ????0.77 |
| ??I-a-f | ??trans-(-)-(3?S，4S，2’R) | ????6387(4974-8203) | ????0.13 |
| ??I-a-g | ??trans-(+)-(3R，4R，2’S) | ????1391(1168-1657) | ????0.58 |
| ??I-a-h | ??trans-(-)-(3R，4R，2’R) | ????9884(6765-14441) | ????0.08 |
Table 2 I-b (R
1=NH
2, R
2/ R
3=OH/H) 8 steric isomer analgesic activities
*
| Compound | Absolute configuration | ????ED 50(μg/Kg) | Potent than (morphine=1) |
| ??I-b-a | ??cis-(-)-(3R，4S，2’R) | ????12.960(10.903-15.406) | ????62.2 |
| ??I-b-b | ??cis-(+)-(3R，4S，2’S) | ????3.126(2.447-3.994) | ????258 |
| ??I-b-c | ??cis-(-)-(3S，4R，2’R) | ????10.0mg/Kg(0/10) | ????- |
| ??I-b-d | ??cis-(+)-(3S，4R，2’S) | ????10.0mg/Kg(0/10) | ????- |
| ??I-b-e | ??trans-(+)-(3S，4S，2’S) | ????1323(945-1853) | ????0.61 |
| ??I-b-f | ??trans-(-)-(3S，4S，2’R) | ????1097(833-1444) | ????0.73 |
| ??I-b-g | ??trans-(+)-(3R，4R，2’S) | ????391.186(324.693-471.296) | ????2.06 |
| ??I-b-h | ??trans-(-)-(3R，4R，2’R) | ????378.739(347.420-412.882) | ????2.12 |
Table 3 I-c (R
1=Cl, R
2/ R
3=OH/H) 8 steric isomer analgesic activities
*
| Compound | Absolute configuration | ????ED 50(μg/Kg) | Potent than (morphine=1) |
| ??I-c-a | ?cis-(-)-(3R，4S，2’R) | ????22.410(19.861-25.286) | ????27.1 |
| ??I-c-b | ?cis-(+)-(3R，4S，2’S) | ????6.028(4.783-8.060) | ????130 |
| ??I-c-c | ?cis-(-)-(3S，4R，2’R) | ????10.0mg/Kg(0/10) | ????- |
| ??I-c-d | ?cis-(+)-(3S，4R，2’S) | ????10.0mg/Kg(0/10) | ????- |
| ??I-c-e | ?trans-(+)-(3S，4S，2’S) | ????254.203(205.708-314.136) | ????3.17 |
| ??I-c-f | ?trans-(-)-(3S，4S，2’R) | ????680.126(586.175-789.134) | ????1.18 |
| ??I-c-g | ?trans-(+)-(3R，4R，2’S) | ????259.867(231.612-291.569) | ????3.10 |
| ??I-c-h | ?trans-(-)-(3R，4R，2’R) | ????1404(1216-1627) | ????0.57 |
Table 4 I-d (R
1=F, R
2/ R
3=O) analgesic activities and the analgesic activity time of 2 steric isomers
*
| Compound | Absolute configuration | ????ED 50mg/Kg，(95％c，L) | Strength ratio morphine=1 | Action time min |
| ??I-d-a | ??cis-(-)-(3R，4S) | ????0.0676(0.0571～0.0800) | ??203 | ??270 |
| ??I-d-b | ??cis-(+)-(3S，4R) | ????10.92(9.89～12.06) | ??1.3 | ??5 |
Table 5 I-e (R
1=F, R
2/ R
3=OH/H) analgesic activities and the action time of 8 steric isomers
*
*: mouse writhing method, subcutaneous administration, morphine analgesia ED
50Be 806 μ g/Kg;
*: mouse hot plate method, subcutaneous administration, morphine analgesia ED
50Be 13.9mg/Kg.
| Compound | Absolute configuration | ????ED 50mg/Kg，(95％c，L) | Strength ratio morphine=1 | Action time min |
| ?I-e-a | ??cis-(-)-(3R，4S，2’R) | ????0.00362(0.00243～0.00539 | ????3840 | ????50 |
| ?I-e-b | ??cis-(+)-(3R，4S，2’S) | ????0.000774(0.000624～0.00142) | ????17958 | ????40 |
| ?I-e-c | ??cis-(-)-(3S，4R，2’R) | ????10(4/10) | ????-- | ????-- |
| ?I-e-d | ??cis-(+)-(3S，4R，2’S) | ????＞10(0/10) | ????-- | ????-- |
| ?I-e-e | ??trans-(+)-(3S，4S，2’S) | ????0.0275(0.0213～0.0353) | ????505 | ????30 |
| ?I-e-f | ??trans-(+)-(3S，4S，2’R) | ????0.0469(0.0372～0.0590) | ????296 | ????40 |
| ?I-e-g | ??trans-(-)-(3R，4R，2’S) | ????0.0403(0.0317～0.0531) | ????345 | ????60 |
| ?I-e-h | ??trans-(-)-(3R，4R，2’R) | ????0.0314(0.0262～0.0376) | ????443 | ????15 |
Embodiment 1S-(+)-4 '-oil of mirbane oxyethane [S-(+)-III]
1000ml tap water, 100g glucose, 10g yeast extract paste and 1g urea are formed nutrient solution, and behind the high-temperature sterilization, cooling inserts geotrichum candidum G38 bacterial classification, and jolting 48 hours is filtered and obtained geotrichum candidum viable bacteria body.The thalline that 150g is wet adds in 1000ml 5% glucose solution, the 3mlDMF solution of Dropwise 5 g (0.025mol) 2-chloro-4 ' nitro-acetophenone, room temperature (24～30 ℃) jolting 18 hours, TLC shows that reaction finishes, leach thalline, thalline and filtrate with the saturated common salt washing, are used NaSO respectively with ethyl acetate extraction for several times
4After the drying,, get faint yellow solid 4.5g (yield 89.5%) in being lower than 35 ℃ down except that desolvating, silicagel column (eluent ethyl acetate: sherwood oil=1: 10) took a morsel, get white solid sample S-(+)-2-chloro-1-(4-nitrophenyl) ethanol, 86～87 ℃ of mp, [α]
D 15+ 37.4 ° of (c1.70CHCl
3), lit.[α]
D 18+ 37.2 ° of (c2.0CHCl
3), ee＞99%,
1HNMR composes same raceme.
Above-mentioned S-(+)-2-chloro-1-(4-nitrophenyl) ethanol 4.0g (0.02mol) is dissolved in few methyl alcohol of trying one's best, under ice bath, drips the 2ml20%NaOH aqueous solution.Methyl alcohol is removed in stirring at room reaction 2 hours, resistates with ethyl acetate extraction after with the washing of NaCl saturated aqueous solution, anhydrous MgSO
4Drying, remove behind siccative and the solvent faint yellow solid, recrystallizing methanol, faint yellow needle-like crystal S-(+)-4 '-oil of mirbane oxyethane 3.0g (yield 91%), mp84-85 ℃, [α]
D 20+ 40.6 °, ee＞99%, { lit.
[80][α]
D 18+ 38.4 ° of (c2.0 CHCl
3).R-(-)-4 '-oil of mirbane oxyethane [R-(-)-III]
Saccharomyces cerevisiae 100g is added 1000ml tap water, 50g glucose and 1g urea to be formed in the nutrient solution, drip the 2mlDMF solution of 4.0g (0.02mol) 2-chloro-4 ' nitro-acetophenone, room temperature (24～30 ℃) jolting 30 hours, TLC shows that reaction finishes, leach thalline, thalline and filtrate are washed anhydrous Na respectively with ethyl acetate extraction for several times with saturated common salt
2SO
4Drying being lower than 35 ℃ down except that desolvating, gets faint yellow solid 2.5g (yield 62.5%), silicagel column (eluent ethyl acetate: sherwood oil=1: 10) took a morsel, white solid sample R-(-)-2-chloro-1-(4-nitrophenyl) ethanol, mp86～87 ℃, [α]
D 20-37.6 ° of (c2.0CHCl
3).
Get 2.0g (0.01mol) R-(-)-2-chloro-1-(4-nitrophenyl) ethanol and be dissolved in few methyl alcohol of trying one's best, drip 2ml20%NaOH solution under ice bath stirs, stirring at room is to reacting completely, remove methyl alcohol, the resistates ethyl acetate extraction is with saturated common salt washing, anhydrous Na
2SO
4Dry.After removing siccative and solvent, obtain faint yellow solid, use recrystallizing methanol, white crystal R-(-)-4 '-oil of mirbane oxyethane 1.32g (yield 89%), mp84～85 ℃, [α]
D 20-40.1 °, ee＞99%, { lit.
[76][α]
D 18-39.31 ° of (c1.99, CHCl
3).Cis-(-)-(3R, 4S, 2 ' R)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines
With 1.52g (8.0mmol) cis-(+)-(3R, 4S)-II is heated to 100 ℃, makes its fusing, adds 1.32g (8.0mmol) R-(+)-phenyl ethylene oxide in 0.5 hour in batches, continued stirring reaction 3 hours, with sherwood oil-ethyl alcohol recrystallization, get faint yellow plate crystal cis-(-)-(3R, 4S, 2 ' R)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines 2.62g, yield 92.3%, mp148～149 ℃, [α]
D 25+ 17.34 ° (c 0.25 MeOH), MS (m/z): 355 (M
+), 337,307,203,160 (base), 132,81;
1HNMR (CDCl
3): δ 1.03 (3H, d, J=7.143-), 1.82 (2H, m), 2.29 (1H, m), 2.35-2.44 (2H, m), (2.56 1H, dd, J=3.30,12.5), 2.63 (2H, m), 2.74 (1H, m), 3.54 (1H, b), 4.81 (H, dd, J=2.7,10.3), 6.6～8.2 (9H, m, Ar-H).Cis-(-)-(3R, 4S, 2 ' R)-N-{1-[2-hydroxyl 2-(4-nitrophenyl) ethyl]-3-methyl-4-piperidyl }-N-Phenylpropionamide (I-a-a)
1.07g (3.0mmol) cis-(-)-(3R, 4S, 2 ' R)-and 3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines is dissolved in the 15ml chloroform, adds the 3.5ml triethylamine under the ice bath cooling, stir, in 30 minutes, drip the 10ml chloroformic solution of the new propionyl chloride that steams of 2.0ml, finish and be heated to 50～60 ℃, stirring reaction 1.5 hours is after the cooling, with saturated common salt washing 2-3 time, anhydrous K
2CO
3Drying is removed siccative and solvent, gets yellow oily liquid.Be dissolved in 90% methanol aqueous solution, add the 2.5g powdered potassium carbonate, the stirring at room reaction, TCL tracks to hydrolysis and finishes, and methyl alcohol is removed in decompression, and resistates is dissolved in the 80ml ether, uses the saturated common salt water washing, anhydrous K
2CO
3Drying is removed siccative and ether, gets the pale yellow oily liquid body, with ethanol-sherwood oil recrystallization, gets faint yellow tabular crystal I-a-a1.1g, and mp166-168 ℃, [α]
D 25-61.86 ° (c0.61, MeOH), yield 89%.IR：3363.3，2982，1645.0，1525.4，1384.0，1074.2，856.3，702；MS?m/z：412(M
+)，363，259(base)，216，203，160，132，77；
1HNMR(CDCl
3)：δ1.04(3H，t，J＝7.42)，1.19(3H，d，J＝7.13)，1.38(1H，b)，1.53(1H，bd，J＝9.9)，1.98(2H，dq，J＝7.5，2.47)，2.32(1H，bt)，2.44(2H，m)，2.52(1H，b)，2.72(1H，b)，2.85(1H，b)，2.98(1H，d，J＝10.12)，4.48(1H，dt，J＝12.91，4.4)，7-8.3(9H，m，Ar-H)。Ultimate analysis (%): C61.67, H6.45, N9.14, theoretical value C61.66, H6.75, N9.38.
All the other compounds are used with quadrat method and are made:
I-a-b:Cis-(+)-(3R, 4S, 2 ' S)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines, faint yellow needle-like crystal, yield 90%, mp155-156 ℃, [α]
D 25+ 27.02 ° (c 0.19, MeOH).
1HNMR(CDCl
3)：δ1.04(3H，d，J＝6.79)，1.82(2H，d，J＝5.16)，2.24(1H，m)，2.33-2.42(2H，m)，2.58(1H?dd，J＝3.5，12.5’)，2.72(1H，d，J＝11.11)，2.92(1H，m)，3.56(H，b)，4.85(1H，dd?J＝3.3，10.3)，6.6-8.2(9H，m，Ar-H)。
I-a-c:Cis-(-)-(3S, 4R, 2 ' R)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines, faint yellow needle-like crystal, yield 93%, mp155-156 ℃, [α]
D 25-26.80 ° (c 0.56, MeOH).
1HNMR composes same I-a-b.
I-a-d:Cis-(+)-(3S, 4R, 2 ' S)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines, faint yellow tabular crystal, yield 90%, mp148-150 ℃, [α]
D 25-17.50 ° (c 0.82, MeOH).
1HNMR composes same I-a-a.
I-a-e:Trans-(+)-(3S, 4S, 2 ' S)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines, faint yellow needle-like crystal, yield 92%, mp133-135 ℃, [α]
D 25+ 63.50 ° (c 0.60, MeOH).MS(m/z)：355(M+)，337，307，203(base)，160，146，132，106；
1HNMR(CDCl
3)：δ1.01(7H，d，J＝6.6)，1.39(1H，ddd，J＝10.5，4.2，3.0)，1.75(1H，m)，2.16-2.25(3H，m)，2.41(1H，t)，2.58(1H，dd，J＝3.6，12.3)，2.85(1H，bd，J＝10.2)，2.97(1H，td，J＝3.5，10.2)，3.16(1H，bd，J＝12.5)，3.38(1H，b)4.81(1H，dd，J＝3.6，10.7)，6.6-8.2(9H，m，Ar-H)。
I-a-f:Trans-(+)-(3S, 4S, 2 ' R)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines, faint yellow tabular crystal, yield 91%, mp135-136 ℃, [α]
D 25+ 50.91 ° (c0.66, MeOH); MS (m/z): 355 (M+), 337,307,203 (base) 160,146,132,106;
1HNMR (CDCl
3): δ 1.04 (3H, d, J=6.6), 1.44 (1H, ddd), 1.70 (1H, m), 1.94 (1H, t, J=11.0), 2.18 (ddd, J=3.0,3.3,12.9), 2.34-2.5 (2H, m), 2.59 (1H, dd, J=3.2,12.6), 2.83 (1H, d, J=10.7), 2.96 (1H, b), 3.18 (1H, dd, J=10.1,2.1), 3.37 (1H, b), 4.90 (1H, dd, J=3.3,10.4), 6.6-8.2 (9H, m, Ar-H).
I-a-g:Trans-(-)-(3R, 4R, 2 ' S)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines, faint yellow tabular crystal, yield 89%, mp135-136 ℃, [α]
D 25-50.81 ° (c 0.14, MeOH).
1HNMR composes same I-a-f
I-a-h:Trans-(-)-(3R, 4R, 2 ' R)-3-methyl isophthalic acid-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-4-anilino piperidines, faint yellow needle-like crystal, yield 92%, mp133-135 ℃, [α]
D 25-63.40 ° (c 0.26, MeOH).
1HNMR composes same I-a-eCis-(-)-(3R, 4S, 2 ' R)-N-{1-[2-hydroxyl-2-(4-aminophenyl) ethyl]-3-methyl-4-piperidyl }-N-Phenylpropionamide (I-b-a)
Getting 1.5g (3.64mmol) I-a-a is dissolved in the 80ml dehydrated alcohol, add the 0.2g10%Pd-C catalyzer, 40 ℃ of following normal pressure hydrogenations 6 hours, filter the back except that desolvating, get colourless oily liquids,, obtain colourless needle-like crystal I-b-a 1.35g with ethyl acetate-sherwood oil recrystallization, mp108～110 ℃, [α]
D 25-58.3 ° of (c1.10, CHCl
3), yield 77%, IR (KBr): 3441 (OH), 3410,3340, (NH
2), 1650.5,1598.9,1520,1499,709.1; MS (m/z): 391 (M
+), 363 (M-H
2O), 259 (base), 216,203,160,145,119,94,77;
1HNMR (CDCl
3): δ 1.0 (3H, t, J=7.4) 1.14 (3H, d, J=6.8) 1.33 (1H, b) 1.50 (1H, b), 1.93 (2H, dq, J=7.5,2.0), 2.37 (4H, B), 2.79 (2H, b), 2.95 (1H, b), 4.48 (1H, dt, J=12.6,4.26), 4.58 (1H, b), 6.6-7.4 (9H, m), ultimate analysis (%): C72.21, H8.23, N10.86, theoretical value C72.40, H8.19, N11.01.All the other compounds are used with quadrat method and are made:
I-b-b:Cis-(+)-(3R, 4S, 2 ' S)-N-{1-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-3-methyl-4-piperidyl }-the N-Phenylpropionamide, faint yellow needle-like crystal (yield 90%), mp111-112 ℃, [α]
D 25+ 67.65 ° (c0.93, MeOH).
1HNMR (CDCl
3): δ 1.00 (3H, t, J=7.9) 1.16 (3H, d, J=6.9), 1.42 (1H, b) 1.48 (1H, b), 1.93 (2H, dq, J=7.5,1.98), 2.16 (1H, b), 2.34 (1H, b), 2.52 (1-H, b) 2.70 (2H, m), 2.79 (1H, and b) 3.07 (1H, b), 4.45 (1H, dt, J=12.0,4.4), 4.78 (1H, b), 7.0-8.2 (9H, m), ultimate analysis (%): C61.84, H6.37, N9.38.
I-b-c:Cis-(-)-(3S, 4R, 2 ' R)-N-{1-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-3-methyl-4-piperidyl }-the N-Phenylpropionamide, faint yellow needle-like crystal (yield 89%), mp110-112 ℃, [α]
D 25-68.34 ° (c 0.61, MeOH), ultimate analysis (%): C61.80, H6.39, N9.21,
1HNMR composes same I-b-b.
I-b-d:Cis-(+)-(3S, 4R, 2 ' S)-N-{1-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-3-methyl-4-piperidyl }-the N-Phenylpropionamide, faint yellow tabular crystal (yield 91%), mp166-168 ℃, [α]
D 25+ 61.26 ° (c 0.70, MeOH) ultimate analysis (%): C61.73, and H6.42, N9.34,
1HNMR composes same I-b-a.
I-b-eHCl:trans-(+)-(3S, 4S, 2 ' S)-N-{1-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-3-methyl-4-piperidyl }-N-Phenylpropionamide hydrochloride, white needle-like crystals, mp235-237 ℃, [α]
D 25+ 52.50 ° (c1.12, MeOH), yield yield 93%.Ultimate analysis (%): C61.56, H6.72, N9.22, theoretical value C61.66, H6.75, N9.38.After the hydrochloride alkalization
1HNMR (CDCl
3): δ 1.01 (3H, t, J=7.6), 1.02 (3H, d, J=7.0), 1.52 (1H, b), 1.76 (1H, d, 3.48), 1.79 (1H, d, J=3.5), 1.95 (2H, q, J=7.61), 2.25 (2H, dd, J=11.4,22.5), 2.44 (1H, tJ=7.7), 2.58 (1H, dd, J=12.68,3.17), 2.91 (1H, bd, J=9.2), 3.20 (1Hbd, J=10.1), 4.56 (1H, b), 4.81 (1H, d, J=7.92), 7.0-8.2 (9H, m, Ar-H).
I-b-fHCl:trans-(+)-(3S, 4S, 2 ' R)-N-{1-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-3-methyl-4-piperidyl } N-Phenylpropionamide hydrochloride, white plates crystal, yield 87%, mp239-242 ℃, [α]
D 25-11.40 ° (c0.87, MeOH).Ultimate analysis (%): C61.62, H6.81, N9.26.After the hydrochloride alkalization
1HNMR (CDCl
3): δ 1.01 (3H, t, J=7.6) 1.07 (3H, d, J=6.59), 1.57 (1H, b), 1.71 (H, bd), 1.78 (1H, dJ=3.30), 1.92 (2H, q, J=6.6) 2.08 (1H, m), 2.32 (1H, t, J=11.60), 2.45 (1H, t, J=11.34), 2.53 (1H, dd, J=12.3,3.57), 2.80 (1H, bd, J=10.5), 3.11 (1H, bd, J=10.61), 4.58 (1H, b), 4.74 (1H, dd, J=3.6,10.58), 7.0-8.2 (9H, m, Ar-H).
I-b-gHCl:trans-(-)-(3R, 4R, 2 ' S) N-{1-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-3-methyl-4-piperidyl } N-Phenylpropionamide hydrochloride, white plates crystal, yield 85%, mp239-242 ℃, [α]
D 25+ 11.12 ° (c0.99, MeOH), ultimate analysis (%): C61.78, H6.47, N9.20;
1HNMR composes same I-b-f.
I-b-hHCl:trans-(-)-(3R, 4R, 2 ' R)-N-{1-[2-hydroxyl-2-(4-nitrophenyl) ethyl]-3-methyl-4-piperidyl }-N-Phenylpropionamide hydrochloride, white needle-like crystals, yield 89%, mp235-237 ℃, [α]
D 25-52.34 ° (c1.50, MeOH), ultimate analysis (%): C61.91, H6.98, N9.34;
1HNMR composes same I-b-e.
Embodiment 2 (S)-(-)-benzyl proline(Pro)
With 5g (0.043mol) (S)-(-)-aqueous sodium hydroxide solution and 0.65g (0.002mol) tetrabutylammonium chloride of proline(Pro), 32ml water, 22ml 2N add in the round-bottomed flask of 100ml successively, stir and drip 6.3ml (0.045mol) benzyl chloride after 5 minutes, be heated to 65 ℃, stirring reaction 2 hours.The aqueous sodium hydroxide solution and the 2.2ml benzyl chlorine that add 5.5ml2N again, continuing at 65 ℃ reacted 1 hour down, cooling transfers to neutrality with the dilute hydrochloric acid of about 6ml1N with the pH value, reduces pressure except that anhydrating, add 50ml ethanol, have solid sodium chloride to separate out, remove by filter, filtrate decompression is removed and is desolvated, get 12g oily crude product (S)-(-)-benzyl proline(Pro), be not further purified.(S)-(-)-the benzyl proline methyl ester
With the 12g (in 0.043mol) of above-mentioned preparation (S)-(-)-benzyl proline(Pro) dissolving crude product is in the 60ml anhydrous methanol, add the 4ml vitriol oil, back flow reaction 18 hours, methyl alcohol is removed in decompression, resistates is dissolved in the 100ml ethyl acetate, wash successively with 100ml water, 100ml saturated sodium bicarbonate aqueous solution, the aqueous sodium hydroxide solution of 100ml2N, saturated sodium-chloride water solution, anhydrous magnesium sulfate drying, filtering and concentrating, getting pale yellow oily liquid body 7.6g, is 80% with (S)-(-)-proline(Pro) calculated yield.Taking a morsel, (eluent is a sherwood oil to silicagel column: ethyl acetate=6: 1), obtain colourless oil liquid, [α]
D 20-74.1 (c1.1, CHCl
3),
1HNMR (CDCl
3): 1.7-2.22 (4H, m), 2.38 (1H, dd, J=8.41,16.61), 3.05 (1H, m), 3.24 (1H, dd, J=6.3,8.60), 3.56 (1H, d, J=12.7), 64 (3H, s), 3.86 (1H, d, J=12.7), 7.23-7.35 (5H, m).(S)-(-)-N-benzyl-2-(phenylbenzene hydroxymethyl)-Pyrrolidine
2.2g (92mmol) magnesium chips and 14.1g (90mmol) bromobenzene are made Grignard reagent in the anhydrous THF of 100ml, be cooled to 0 ℃, drip 6.6g (30mmol) (S)-(-)-the 40ml tetrahydrofuran solution of benzyl proline methyl ester, dropwised in about 30 minutes, 10 hours post-heating to 35 of stirring at room reaction ℃ reacted 2 hours.THF is removed in decompression, after the dilution of adding 200ml ether, adds the 100ml saturated aqueous ammonium chloride with decomposition reactant under the ice bath cooling, stir after 20 minutes, tell ether layer, use the saturated sodium-chloride water washing, anhydrous magnesium sulfate drying, filter, removal of solvent under reduced pressure, residue gets white plates crystal 8.75g with ethyl acetate-normal hexane recrystallization, mp114-116 ℃, yield 86%.MS(m/z)：344(M+1)，254，206，160，70(base)。
1HNMR(CDCl
3)：1.62(2H，m)，1.76(1H，m)，1.96(1H，m)，2.36(1H，dd，J＝9.34，16.61)，2.92(1H，m)，3.03(1H，d，J＝12.63)，3.23(1H，d，J＝12.63)，3.98(1H，q，J＝4.67)，4.95(1H，s)，7.0-7.80(15H，m)。(S)-(-)-2-(phenylbenzene hydroxymethyl)-Pyrrolidine
1.0g (2.9mmol) (S)-(-)-N-benzyl-2-(phenylbenzene hydroxymethyl)-Pyrrolidine is dissolved in 50ml ethanol, add 0.2g 10% palladium carbon and 0.5ml glacial acetic acid, in 40 ℃ of following normal pressure hydrogenations 12 hours, remove by filter palladium carbon, the filter cake methanol wash of heat, filtrate decompression is removed and is desolvated, residue is washed with 10% aqueous sodium hydroxide washes after adding the 30ml acetic acid ethyl dissolution, anhydrous magnesium sulfate drying, filter,, use the alcohol-water recrystallization except that getting oily liquids after desolvating, get colourless acicular crystal 0.62g yield 84.5%, mp78-79.5 ℃.[α]
D 20-57.1°(c1.1，MeOH)，MS(m/z)：254[M+1]，236，206，166，107，79，70(base)；
1HNMR(CDCl
3)：1.57-1.75(5H，m)，3.00(2H，m)，4.27(1H，t，J＝7.55)，7.15-7.59(10H，m)。(S)-(-)-and tetrahydrochysene-1-methyl-3,3-phenylbenzene-1H, 3H-pyrrolo--[1,2, c] [1,3,2] oxazole borines
[(S)-(-)-V]
With 0.759g (3mmol) (S)-(-)-2-(phenylbenzene hydroxymethyl)-Pyrrolidine is dissolved in the 10ml dry toluene, is cooled to 5 ℃, at N
2Protection adds down 0.251g (2mmol) trimethylboroxin, and the adularescent solid is separated out, and continues 25 ℃ of stirring reactions 40 minutes.Distillation is (at N after adding the 50ml dry toluene
2Protection is down), with water, methyl-boron-dihydroxide and the excessive trimethylboroxin of removing generation.At last reaction solution is distilled to surplus 3ml, the concentration of catalyzer this moment [(S)-(-)-V] is about 1M, charges into nitrogen, airtight preservation.Get the toluene solution of the above-mentioned catalyzer of 1ml, decompression is removed toluene and is obtained the 280mg white solid, mp80-82 ℃ of [lit
[18].mp74-87 ℃],
1HNMR (CDCl
3): δ 0.40 (3H, s), 0.74-0.95 (1H, m), 1.54-1.99 (3H, m), 3.00-3.16 (1H, m), 3.33-3.45 (1H, m), 4.41 (1H, dd, J=5.8,10.0), 7.14-7.15 (10H, m, Ar-H).(R)-(+)-and tetrahydrochysene-1-methyl-3,3-phenylbenzene-1H, 3H-pyrrolo--[1,2, c] [1,3,2] oxazole borines
[R-(+)-V]
With (R)-proline(Pro) is raw material, is prepared into the toluene solution of 1M R-(+)-V according to the method for preparation (S)-(-)-V, mp80-82 ℃,
1HNMR is with (S)-(-)-V.S-(+)-4 '-chloro-phenyl-oxyethane
Toluene solution and the anhydrous THF of 4ml of 0.5ml 1M (S)-(-)-V are cooled to-10 ℃ under nitrogen protection, add 1ml THFBH
3(1M), Dropwise 5 70mg (3mmol) 2, the 4ml anhydrous THF solution of 4 '-dichlorophenyl ethyl ketone, and drip 2ml THFBH simultaneously
3(1M) solution.Finish the back this temperature stirring reaction 15 minutes, be warming up to 15 ℃ of reactions 10 minutes.Reaction mixture is ice-cold to-10 ℃, add 1ml methyl alcohol, stirred 10 minutes, add saturated hydrogenchloride-diethyl ether solution of 0.5ml again, decompression except that desolvating, adds the 15ml anhydrous diethyl ether down, stir solid, be cooled to 0 ℃, the elimination solid.Filtrate water and saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying filters, and removes and desolvates, and obtains colourless oil liquid.Be dissolved in the 8ml methyl alcohol, under 0 ℃ of stirring, drip the aqueous sodium hydroxide solution of 1.5ml 20%, finish and stirred 2.5 hours.TCL follows the tracks of and reacts completely, methyl alcohol is removed in decompression, uses ether extraction, the saturated sodium-chloride water solution washing, anhydrous magnesium sulfate drying, filter, remove and desolvate, obtain colourless oil liquid, (eluent is a methylene dichloride: sherwood oil=3: 7) through silica gel column chromatography, get colourless oil liquid 404mg, yield 87%, [α]
D 20+ 21.00 ° of (c1.433, CHCl
3) (lit
[21], [α]
D 20+ 19.8 ° of (c1.16, CHCl
3);
1HNMR (CDCl
3): δ 2.74 (1H, dd, J=5.55,2.61), 3.15 (1H, dd, J=5.55,4.12), 3.83 (1H, dd, J=2.62,4.12), 7.16-7.35 (4H, m).Cis-(+)-(3R, 4S, 2 ' R)-3-methyl isophthalic acid-(2-hydroxyl-2-(4-chloro-phenyl-) ethyl)-4-anilino piperidines
With 285mg (1.5mmol) cis-(+)-(3R, 4S)-II is dissolved in 1ml toluene, add 0.232g (1.5mmol) (S)-4 '-chloro-phenyl-oxyethane, in about 5 hours of 90 ℃ of stirring reactions, TCL follows the tracks of and reacts completely, toluene is removed in the decompression of cooling back, and residue gets colourless needle-like shape crystal c is-(+)-(3R with ethyl acetate-sherwood oil recrystallization, 4S, 2 ' R)-and 3-methyl isophthalic acid-(2-hydroxyl-2-(4-chloro-phenyl-) ethyl)-4-anilino piperidines 380mg, mp122-123 ℃, yield 92%.[α]
D 20+49.92°(c1.21，CHCl
3)，MS(m/z)：344.1[M+1]，326，203，160，118，84；
1HNMR(CDCl
3)：1.03(2H，d，J＝7.14)，1.82(2H，m)，2.27(1H，b)，2.42(3H，m)，2.61(2H，s)，2.72(1H，b)，3.58(2H，b)，4.70(1H，d)，6.60-7.20(9H，m)。Cis-(+)-(3R, 4S, 2 ' S)-N-[1-[2-hydroxyl-2-(4-chloro-phenyl-) ethyl]-3-methyl-4-piperidyl]-N-Phenylpropionamide (I-c-a)
0.55g cis-(+)-(3R, 4S, 2 ' R)-3-methyl isophthalic acid-(2-hydroxyl-2-(4-chloro-phenyl-) ethyl)-4-anilino piperidines is dissolved in the 50mL dry toluene, adds 1ml and newly steam propionyl chloride, reflux 4.5 hours.Cooling, alkalize with strong aqua after adding 100ml water, the water layer ethyl acetate extraction merges organic phase, uses anhydrous magnesium sulfate drying, remove siccative and solvent, resistates be dissolved in 50ml contain 10% water methanol solution in, add 1g salt of wormwood, stirring at room reaction 2 hours, TCL follows the tracks of and reacts completely, elimination salt of wormwood, resistates is dissolved in the 80mL ether behind the concentrating under reduced pressure, washs with saturated sodium-chloride water solution, the Anhydrous potassium carbonate drying, filter, concentrate the back residue, get white, needle-shaped crystals I-c-a 0.59g with ethyl acetate-sherwood oil recrystallization, mp132-133 ℃, yield 92%.[α]
D 25+61.2°(c1.45，CHCl
3)。MS(m/z)：401(M
+)，369，259(base)，216，203，160，132，110；IR(cm
-1)：3405.7，2939.0，2788.6，1656.6，1549.9，1496.5，1373.1，707.8；
1HNMR(CDCl
3)：0.98(3H，t，J＝7.60)，1.15(3H，d，J＝7.14)，1.47(2H，b)1.92(2H，q，J＝7.12)，2.17(1H，b)，2.42(2H，b)，2.71(1H，b)，2.77(2H，t，J＝3.3)，3.06(1H，d，J＝10.44)，4.41(1H，dt，J＝12.14，4.53)，4.68(1H，b)，7.0-7.50(9H，m，Ar-H)。Ultimate analysis (%): C68.89, H7.33, N6.90; Theoretical value C68.89, H7.29, N6.99.
All the other compounds are used with quadrat method and are made:
I-c-b:cis-(-)-(3R, 4S, 2 ' R)-N-[1-[2-hydroxyl-2-(4-chloro-phenyl-) ethyl]-3-methyl-4-piperidyl]-the N-Phenylpropionamide), white plates crystallization, mp132-133 ℃, [α]
D 25-59.0 ° of (c1.295, CHCl
3).MS (m/z): 401 (M
+), 369,259 (base), 216,203,160,132,110; IR (cm
-1): 3403.8,2939.0,2804.0,1643.1,1594.9,1494.6,1384.7,820.3,708;
1HNMR (CDCl
3): 1.01 (3H, t, J=7.4), 1.19 (3H, d, J=7.14), 1.43 (1H, b), 1.62 (1H, b), 1.95 (2H, dq, J=7.14,1.65), 2.52 (3H, b), 2.88 (2H, b), 3.09 (1 H, b), 4.45 (1H, dt, J=6.50,5.0), 7.0-7.5 (9H, m, Ar-H); Ultimate analysis (%): C69.01, H7.16, N6.96.
I-c-c:cis-(+)-(3S, 4R, 2 ' S)-N-[1-[2-hydroxyl-2-(4-chloro-phenyl-) ethyl]-3-methyl-4-piperidyl]-the N-Phenylpropionamide, white plates crystallization, mp132-133 ℃, [α]
D 25+ 59.80 ° of (c0.66, CHCl
3).MS (m/z): 401 (M
+), 369,259 (base), 216,203,160,132,110; IR (cm
-1): 3403.8,2939.0,2804.0,1643.1,1594.9,1494.6,1384.7,820.3,70.8;
1HNMR composes same I-c-b; Ultimate analysis (%): C68.80, H7.31, N6.90.
I-c-d:cis-(-)-(3S, 4R, 2 ' R)-N-[1-[2-hydroxyl-2-(4-chloro-phenyl-) ethyl]-3-methyl-4-piperidyl]-the N-Phenylpropionamide, white, needle-shaped crystals, mp132-133 ℃, [α]
D 25-59.2 ° of (c0.90, CHCl
3).MS (m/z): 401 (M
+), 369,259 (base), 216,203,160,132,110; The IR spectrum reaches
1HNMR composes same I-c-a; Ultimate analysis (%): C69.06, H7.21, N6.98.
I-c-eHCl:trans-(+)-(3S, 4S, 2 ' S)-N-[1-[2-hydroxyl-2-(4-chloro-phenyl-) ethyl]-3-methyl-4-piperidyl]-N-Phenylpropionamide hydrochloride, white plates crystallization, mp 220-222 ℃, [α]
D 25+ 47.6 ° of (c0.81, CHCl
3).MS(m/z)：401(M
+)，369，259(base)，216，203，160，132，110；IR(cm
-1)：3533.0，3151.2，2971.8，2514.8，1662.4，1089.6，703.9。After the hydrochloride alkalization
1HNMR (CDCl
3): 1.03 (3H, t, J=7.40), 1.04 (3H, d, J=6.05), 1.63 (1H, b), 1.80 (1H, dd, 12.9,3.02), 1.92 (1H, t, 6.15), 1.97 (2H, q, J=7.42), 2.33 (1H, t, J=11.25), (2.38 1H, dd, J=11.1,7.94), 2.58 (2H, m), 3.07 (1H, d, J=13.91), 3.31 (1H, d, J=10.43), 4.81 (1H, dd, J=7.55,3.02), 7.0-7.50 (9H, m, Ar-H).Ultimate analysis (%): C63.09, H6.86, N6.30; Theoretical value: C63.15, H6.91, N6.40.
I-c-fHCl1/2H
2O:trans-(+)-(3S, 4S, 2 ' R)-N-[1-[2-hydroxyl-2-(4-chloro-phenyl-) ethyl]-3-methyl-4-piperidyl]-N-Phenylpropionamide hydrochloride, white needle-like crystals, mp180-182 ℃, [α]
D 25+ 5.0 ° of (c1.42, CHCl
3).IR(cm
-1)：3241.8，2793.1，2515.3，1652.7，1089.6，705.8。Hydrochloride alkalization back MS:401 (M
+), 369,259 (base), 216,203,160,132,110;
1HNMR (CDCl
3): 1.03 (3H, t, J=7.56), 1.08 (3H, d, J=6.32), 1.59 (1H, b), 1.79 (2H, db, J=9.61), 1.98 (3H, q, J=7.40), 2.30 (1H, b), 3.00 (1H, b), 3.23 (1H, b), 4.60 (1H, b), 4.80 (1H, b), 7.0-7.5 (9H, m, Ar-H).Ultimate analysis (%): C62.07, H7.08, N6.18; Theoretical value: C61.88, H7.00, N6.27.
I-c-gHCl1/2H
2O:trans-(-)-(3R, 4R, 2 ' S)-N-[1-[2-hydroxyl-2-(4-chloro-phenyl-) ethyl]-3-methyl-4-piperidyl] N-Phenylpropionamide hydrochloride, white needle-like crystals, mp180-182 ℃, [α]
D 25-4.70 ° of (c1.08, CHCl
3).IR (cm
-1): 3241.8,2793.1,2515.3,1652.7,1089.6,705.8; Ultimate analysis (%): C62.13, H6.99N6.25; Theoretical value: C61.88, H7.00, N6.27.MS,
1HNMR composes same I-c-f.
I-c-hHCl:trans-(-)-(3R, 4R, 2 ' R) N-[1-[2-hydroxyl-2-(4-chloro-phenyl-) ethyl]-3-methyl-4-piperidyl] N-Phenylpropionamide hydrochloride hydrochloride, white plates crystallization, mp220-222 ℃, [α]
D 25-45.0 ° of (c0.69, CHCl
3).MS,
1HNMR composes same I-c-e, ultimate analysis (%): C63.20, H6.89N6.31; Theoretical value: C63.15, H6.91, N6.40.
Embodiment 3Cis-(-)-(3R, 4S)-N-[1-[2-oxygen-2-(4-fluorobenzene ethyl)-3-methyl]-the 4-piperidyl]-N-Phenylpropionamide (I-d-a)
With 1.0g cis-(+)-(3R, 4S)-II, 8.0g the potassiumiodide of Anhydrous potassium carbonate and catalytic amount adds in the 25ml dry toluene, after the stirred for several minute, add 1.14g 4 '-fluoro-2-bromoacetophenone, room temperature reaction 1 hour filters, and solids with the dry toluene washing for several times, add the fresh distillatory propionyl chloride of 2.0ml in the filtrate, back flow reaction 5 hours, the saturated potassium carbonate solution washing is used in cooling, organic layer 1N hydrochloric acid extraction 3-4 time, the sour water layer alkalizes with potash solid, ether extraction, Anhydrous potassium carbonate drying, filtering and concentrating, residue salt manufacturing hydrochlorate, ethanol-ethyl acetate-sherwood oil recrystallization gets white plates crystallization I-d-aHCl 0.75g, mp236-238 ℃, [α]
D 25-6.96 (c0.39, MeOH), yield 34%.Ultimate analysis (%): C 65.88, and H 6.85, and N 6.74; Theoretical value C 65.95, and H 6.69, and N 6.69.All the other compounds are used with quadrat method and are made:
I-d-bHCl:cis-(+)-(3S, 4R)-suitable-N-[1-[2-oxygen-2-(4-fluorobenzene ethyl)]-3-methyl-4-piperidyl]-N-Phenylpropionamide hydrochloride, white plates crystallization, mp236-238 ℃, yield 36%, [α]
D 25+ 6.73 (c0.52, MeOH).Ultimate analysis (%): C 65.87, and H 6.84, and N 6.67; Theoretical value C 65.95, and H 6.69, and N 6.69.Cis-(-)-(3R, 4S, 2 ' R)-N-[1-[2-hydroxyl-2-(4-fluorophenyl) ethyl]-3-methyl-4-piperidyl]-N-Phenylpropionamide (I-e-a) and Cis-(+)-(3R, 4S, 2 ' S)-N-[1-[2-hydroxyl-2-(4-fluorophenyl) ethyl]-3-methyl-4-piperidyl]-N-Phenylpropionamide (I-e-b)
With 1.0g cis-(+)-(3R, 4S)-potassiumiodide of II, 8.0g Anhydrous potassium carbonate and catalytic amount adds in the 25ml chloroform, after the stirred for several minute, 1.14g add 4 '-fluoro-2-bromoacetophenone, room temperature reaction 1 hour filters, and filtrate decompression is concentrated into dried, residue adds the 0.5g sodium borohydride, back flow reaction 2 hours after using the 60ml dissolve with methanol.Solvent is removed in decompression, adds behind the water with extracted with diethyl ether for several times, and the Anhydrous potassium carbonate drying is filtered, and concentrates, and residue is dissolved in toluene, adds the 3.0ml propionyl chloride, back flow reaction 5 hours.Cool off the back and wash with wet chemical, the Anhydrous potassium carbonate drying is filtered, and concentrates, and gets the diastereo-isomerism mixture of dipropyl acylate.Mixture adding 2.5g salt of wormwood and 25ml contain the methyl alcohol of 10% water, stirring at room reaction 20 hours.Suction filtration concentrates, and adds behind the water with extracted with diethyl ether for several times the Anhydrous potassium carbonate drying, filtering and concentrating gets the mixture of I-e-a and I-e-b, carries out fractional crystallization with sherwood oil, gets I-e-b (separating out earlier) 0.49g, mp124-126 ℃, I-e-a (afterwards separating out) 0.41g, mp133-135 ℃, total recovery 44.6%.
I-e-a: the heavy colourless acicular crystal of matter, mp133-135 ℃, [α]
D 25-29.78 (c0.45, MeOH).Ultimate analysis (%): C 72.00, and H 7.48, and N 7.38; Theoretical value C 71.88, and H 7.55, and N 7.29.
1HNMR(CDCl
3)：δ1.01(3H，t，J＝7.5Hz，10-CH
3)，1.16(3H，d，J＝7.1Hz，11-CH
3)，1.35(1H，d，5e-H，J＝13.4Hz)，1.46(1H，dq，5a-H，J＝13.3Hz，4.2Hz)，1.93(2H，q，9-CH
2，J＝7.SHz)，2.36(4H，m，2a-H，6a-H，1’-CH
2)，2.69(1H，d，6e-H，J＝10.7Hz)，2.82(1H，br，3e-H)，2.94(1H，d，2e-H，J＝11.5Hz，)，4.44(1H，dt，J＝12.9Hz，4.3Hz)，4.63(1H，dd，J＝7.1Hz，3.2Hz)，6.98-7.93(9H，m，Ph-H).
I-e-b: the cotton-shaped white crystals of lightweight, mp124-126 ℃, [α]
D 25+ 19.81 (c0.31, MeOH).Ultimate analysis (%): C 71.90, and H 7.85, and N 7.32; Theoretical value C 71.88, and H 7.55, and N 7.29.
1HNMR(CDCl
3)：δ1.01(3H，t，J＝7.4Hz，10-CH
3)，1.17(3H，d，J＝7.1Hz，11-CH
3)，1.36(1H，br，5e-H)，1.43(1H，br，5a-H)，1.94(2H，q，J＝7.6Hz，9-CH
2)，2.11(1H，br，6a-H)，2.38(2H，br，1’-H)，2.66(2H，br，2e-H，2a-H)，2.76(1H，bR，3e-H)，3.04(1H，br，6e-H)，3.99(1H，br，OH)，4.43(1H，dt，4a-H，J＝12.6Hz，4.3Hz)，4.63(1H，br，2’-H)，6.97-7.93(9H，m，Ph-H)。All the other compounds are used with quadrat method and are made:
I-e-c:cis-(-)-(3S, 4R, 2 ' R)-N-[1-[2-hydroxyl-2-(4-fluorophenyl) ethyl]-3-methyl-4-piperidyl]-the N-Phenylpropionamide, the cotton-shaped white crystals of lightweight, mp124-125 ℃, [α]
D 25-19.53 (c0.83, MeOH), ultimate analysis (%): C 71.93, and H 7.42, and N 7.43; Theoretical value C 71.88, and H 7.55, N7.29.
1HNMR composes same I-e-b.
I-e-d:cis-(+)-(3S, 4R, 2 ' S)-N-[1-[2-hydroxyl-2-(4-fluorophenyl) ethyl]-3-methyl-4-piperidyl]-the N-Phenylpropionamide, the heavy colourless acicular crystal of matter, mp133-135 ℃, [α]
D 25+ 27.77 (c0.66, MeOH), yield 28.7%.Ultimate analysis (%): C 71.83, and H 7.46, and N 7.30; Theoretical value C71.88, H 7.55, and N 7.29.
1HNMR composes same I-b-a.
I-e-eHCl:trans-(+)-(3S, 4S, 2 ' S)-N-[1-[2-hydroxyl-2-(4-fluorophenyl) ethyl]-3-methyl-4-piperidyl]-N-Phenylpropionamide hydrochloride, mp224-226 ℃, [α]
D 25+ 29.58 (c0.41, MeOH), ultimate analysis (%): C 65.73, and H 7.30, and N 6.64; Theoretical value C 65.64, and H 7.13, and N 6.66.
1HNMR(CDCl
3)：δ0.98(3H，t，J＝7.4Hz，10-CH
3)，1.06(3H，dd，J＝6.5Hz，11-CH
3)，1.85(1H，m，5a-H)，1.96(2H，q，J＝7.4Hz，9-CH
2)，2.08(1H，m，5e-H)，2.34(1H，m，3a-H)，2.68(1H，q，2a-H)，3.02(2H，m，6a-H，1’-H)，3.12(1H，m，1’-H)，3.75(2H，m，H-6e，H-2e)，4.77(1H，m，4a-H)，5.34(1H，t，J＝9.6Hz，2’-H)，6.97-7.39(9H，m，Ph-H)，11.4(1H，s，NH)。
I-e-fHCl:trans-(+)-(3S, 4S, 2 ' R)-N-[1-[2-hydroxyl-2-(4-fluorophenyl) ethyl]-3-methyl-4-piperidyl]-N-Phenylpropionamide hydrochloride, mp223-224 ℃, [α]
D 25+ 25.56 (c0.67, MeOH), ultimate analysis (%): C 65.60, and H 7.28, and N 6.66; Theoretical value C 65.64, and H 7.13, and N 6.66.
1HNMR(CDCl
3)：δ0.98(3H，t，J＝7.4Hz，10-CH
3)，1.06(3H，dd，J＝6.5Hz，11-CH
3)，1.86(1H，m，5a-H)，1.96(2H，q，J＝7.4Hz，9-CH
2)，2.06(1H，m，5e-H)，2.37(1H，m，3a-H)，2.67(1H，q，2a-H)，3.02(2H，m，6a-H，1’-H)，3.13(1H，m，1’-H)，3.75(2H，m，6e-H，2e-H)，4.77(1H，m，4a-H)，5.35(1H，t，J＝7.8Hz，2’-H)，6.97-7.40(9H，m，Ph-H)，11.4(1H，s，NH)。
I-e-gHCl:trans-(-)-(3R, 4R, 2 ' S) N-[1-[2-hydroxyl-2-(4-fluorophenyl) ethyl]-3-methyl-4-piperidyl] N-Phenylpropionamide hydrochloride, mp223-224 ℃, [α]
D 25-26.84 (c0.61, MeOH), total recovery 43.6%, ultimate analysis (%): C 65.63, and H 7.21, and N 6.67; Theoretical value C 65.64, and H 7.13, and N 6.66.
1HNMR composes same I-e-f.
I-e-hHCl:trans-(-)-(3R, 4R, 2 ' R)-N-[1-[2-hydroxyl-2-(4-fluorophenyl) ethyl]-3-methyl-4-piperidyl] N-Phenylpropionamide hydrochloride, mp224-226 ℃, [α]
D 25-29.14 (c0.52, MeOH), ultimate analysis (%): C 65.67, and H 7.26, and N 6.75; Theoretical value C 65.64, and H 7.13, and N 6.66.
1HNMR composes same I-e-e.
The absolute configuration of nitro ohmefentanyl and fluorine ohmefentanyl is proved conclusively through the x-diffraction.
Claims (13)
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105061282A (en) * | 2015-07-28 | 2015-11-18 | 黑龙江省科学院石油化学研究院 | Method for hydrogenolysis synthesis of alpha,alpha-diphenyl-2-pyrrolidine methanol |
| WO2016096126A1 (en) * | 2014-12-15 | 2016-06-23 | Laboratorios Del Dr. Esteve, S.A. | 1-methylpyrazole-piperazine compounds having multimodal activity against pain |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2016096126A1 (en) * | 2014-12-15 | 2016-06-23 | Laboratorios Del Dr. Esteve, S.A. | 1-methylpyrazole-piperazine compounds having multimodal activity against pain |
| US10189828B2 (en) | 2014-12-15 | 2019-01-29 | Laboratorios Del Dr. Esteve S.A. | 1-methylpyrazole-piperazine compounds having multimodal activity against pain |
| CN105061282A (en) * | 2015-07-28 | 2015-11-18 | 黑龙江省科学院石油化学研究院 | Method for hydrogenolysis synthesis of alpha,alpha-diphenyl-2-pyrrolidine methanol |
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