Tetrahydroprotoberberine compounds, the synthetic method and the use thereof

Technical feild

The present invention relates to novel tetrahydroprotoberberines. The compounds possess valuable therapeutic properties and are suitable, especially, for treating diseases that respond to modulation of dopamine receptors, such as schizophrenia, parkinsonism, hyperactivity disorder or migraine et.al.

Background art

Recently, the pathogenesis of schizophrenia has been suggested to involve dysfunction of dopamine D ₁ receptors in the medial prefrontal cortex (mPFC). Which is resulted in dopamine D ₂ receptor hyperactivity in subcortical regions such as the ventral tegmental area (VTA) and the nucleus accumbens (NAc). D ₁ receptors dysfunction is involved in the negative symptoms of schizophrenia whereas the D ₂ receptors hyperactivity results in the positive symptoms of this disorder. According to this new hypothesis, an effective antipsychotic drug should have both Dj receptor agonist and D ₂ receptor antagonist dual actions.

Tetrahydroprotoberberine analogues (THPBs) have this dual actions, including /-Stepholidine (/-SPD) and /-chloroscoulerine (ZL94112235.2 , CN03151464.2). /-SPD is an active ingredient of the Chinese herb Stephania. /-CSL is a derivative of /-SPD. In preliminary clinic studies, /-SPD showed favorable activity and few side effects in the treatment of schizophrenia. So, the efficacy of THPBs for neuron system disease espacilly schizophrenia merits further investigation.

Disclosure Of The Invention

The invention is based on the object of providing compounds of THPBs, as well as its pharmacologically acceptable salts and solvates, which act as highly affinity dopamine receptor ligands.

The present invention also relates to a preparation method of compounds of THPBs.

The present invention also relates to a method for treating disorder which respond to influencing by dopamine D ₁ and D ₂ receptor. And a method comprise administering an effective amount of at least one THPBs of the formula (I) and/or at least one physiologically acceptable salt of formula(I) to a subject in need thereof.

The present invention relates to the compounds of formula (I), pharmacologically acceptable salts and solvates:

( I )

Wherein

R is H, halogen or cyano;

Each of R ₁ , R ₃ , R ₄ is selected from H, C ₁ -C ₁₂ alkyl, (CH ₂ CH ₂ O) _n R ₆ (n=l~3), amino acid or N-protected amino acid, COR ₇ , SO ₂ R ₆ , SO ₂ NR ₉ R ₁ O, or R ₁ and R ₂ together form (CH ₂ ) _: ] , n is 1 or 2; when R ₁ , R ₃ , R ₄ is C ₁ -C ₁₂ alkyl, the alkyl is saturated or unsaturated alkyl, linear chain C ₁ -C ₁₂ alkyl, branched chain C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ cycloalkyl, C ₁ -C ₁₂ alkyl substituted by aryl, COOR ₆ or CONR ₉ R ₁₀ ; when R ₁ , R ₃ , R ₄ is amino acid or N-protected amino acid, which is D-, L- or DL-amino acid or N-protected amino acid; the protecting groups is selected from Boc, Cbz or other protected group used in amino acid; R ₆ is selected from H, C ₁ -C ₃ alkyl or alkyl substituted by aryl; R ₇ is selected from C ₁ -C ₁₂ alkyl, alkyl substituted by (CH ₂ CH ₂ O) _n R ₆ (n=l~3), alkoxy, COR ₈ , (CH ₂ ) _n NR ₉ R ₁₀ , substituted aryl, unsubstituted aryl, heterocyclic radical selected from imidazolyl, pyrazolyl, pyrrolidinyl, pyridinyl; when R ₇ is C ₁ -C ₁₂ alkyl, the alkyl is saturated or unsaturated alkyl, linear chain C ₁ -C ₁₂ alkyl, branched chain C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ cycloalkyl, C ₁ -C ₁₂ alkyl substituted by carbonyl, phenyl, substituted phenyl or substituted aryl heterocyclic radical; R ₈ is selected from H, alkyl, alkoxy or aryl; R ₉ and R ₁₀ is selected independently from H, C ₁ -C ₄ alkyl substituted by C ₃ -C ₅ cycloalkyl or Cj-C ₄ alkoxy, or form heterocyclic radical selected from azacyclobutyl, pyrrolidinyl,

A Ul/ UH ZiUUU I \J \J 1 O \J i. piperidyl, piperazinyl or morpholinyl;

R ₂ is selected from H ₅ C ₁ -C ₃ alkyl, or R ₁ and R ₂ together form (CH ₂ ) _n , n is 1 or 2;

R ₅ is H, O, C ₁ -C ₃ alkyl, substituted C ₁ -C ₃ alkyl, halogen or aryl, or there is not

R ₅ .

In the definition mentioned above, halogen is F, Cl, Br or I; any two OfR ₁ , R ₂ , R ₃ , R ₄ are same or different group mentioned above.

In particular, when R is H, R ₁ -R ₄ is limited as follow:

When R ₁ is H and R ₂ =R ₃ =CH ₃ , R ₄ is unsubstituted C ₂ -C ₁₂ alkyl, substituted C ₂ -C ₁₂ alkyl, (CH ₂ CH ₂ O) _n R ₆ (n=l~3), amino acid or N-protected amino acid, COR ₇ , SO ₂ R ₆ or SO ₂ NR ₉ R ₁₀ .

When R ₁ is H and R ₂ =R ₄ =CH ₃ , R ₃ is unsubstituted C ₂ -C ₁₂ alkyl, substituted C ₂ -C ₁₂ alkyl, (CH ₂ CH ₂ O) _n R ₆ (n=l~3), amino acid or N-protected amino acid, COR ₇ , SO ₂ R ₆ or SO ₂ NR ₉ R ₁₀ .

When R ₁ is CH ₃ , R ₂ is CH ₃ , and one of R ₃ and R ₄ is unsubstituted C ₂ -C ₁₂ alkyl, substituted C ₂ -C ₁₂ alkyl, (CH ₂ CH ₂ O) _n R ₆ (n=l~3), amino acid or N-protected amino acid, COR ₇ , SO ₂ R ₅ or SO ₂ NR ₉ R ₁₀ .

When R ₁ is CH ₂ Ph, one of R ₃ and R ₄ is unsubstituted C ₂ -C ₁₂ alkyl, substituted C ₂ -C ₁₂ alkyl, (CH ₂ CH ₂ O) _π R ₆ (n=l~3), amino acid or N-protected amino acid, COR ₇ , SO ₂ R ₆ or SO ₂ NR ₉ R ₁₀ .

When R ₁ and R ₂ together form CH ₂ , R ₃ or R ₄ can't be selected from H, CH ₃ , C ₂ H ₅ or COCH ₃ at the same time.

When R is halogen, the compounds described in this invention exclude followed known compounds:

2,9-dihydroxy-3 , 10-dimethoxy- 12-chloro-5,8, 13,13 a-tetrahydro-6H-dibenzo [a, g] quinolizine;

2, 10-dihydroxy-3 ,9-dimethoxy- 12-chloro-5 ,8, 13,13 a-tetrahydro-6H-dibenzo[a, g] quinolizine;

2,3,9, 10-tetramethoxy- 12-chloro-5,8, 13, 13a-tetrahydro-6#-dibenzo[a, g] quinolizine;

2,9-dihydroxy-3 , 10-dimethoxy- 12-bromo-5,8, 13 , 13a-tetrahydro-6H-dibenzo[a, g] quinolizine;

2,10-dihydroxy-3,9-dimethoxy-12-bromo-5,8,13,13a-tetrahydro- 6H-dibenzo[a _; g] quinolizine;

3 ,9-dihydroxy-2, 10-dimethoxy- 12-bromo-5 ,8, 13,13 a-tetrahydro-6H-dibenzo[a, g]quinolizine;

9, 10-dihydroxy-2,3 -dimethoxy- 12-bromo-5,8, 13,13 a-tetrahydro-6H-dibenzo [a, g] quinolizine;

2,3,9,10-tetramethoxy- 12-bromo-5 ,8, 13,13 a-tetrahydro-6H-dibenzo [a, g] quinolizine;

2,9-dihydroxy-3 , 10-dimethoxy- 12-flouro-5, 8, 13,13 a-tetrahydro-6f/-dibenzo [a, g] quinolizine;

2,9-dihydroxy-3, 10-dimethoxy- 12-iodo-5,8, 13, 13a-tetrahydro-6H-dibenzo[a, g] quinolizine;

2,3-methylenedioxyl-9-hydroxy-10-methoxy-12-chloro-5,8,13 ,13a-tetrahydro-6 H-dibenzo[a, g]quinolizine;

2,3-methylenedioxyl-9-hydroxy-10-methoxy-12-bromo-5,8,13, 13a-tetrahydro-6 H-dibenzo[a, gjquinolizine.

Formula (I) has one or several chiral carbons. So the chiral isomers exist, including enantiomers, unenantiomers or its mixture. This invention including the R-, and S- enantiomers and its mixture. The enantiomer can be separated by optical resolution with chemical method or separated by chiral HPLC. It also can be obtained by asymmetry synthesis.

The present invention relates to radioactivity derivatives of formula (I), which is suitable for biological studies.

The present invention also relates to the physiologically acceptable acid addition salts and alkli derivatives of formula (I). The acid addition salts are salts of the compounds of formula (I) with acid, including hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, cabonic acid, organic sulfonic acid. The alkali

derivatives is salts obtained by reacting the compounds of formula (I) with alkali, especially alkali metal derivatives, including natrium or potassium derivatives.

In the preferred embodiments of the compounds of formula (I), R ₁ is H, COR ₇ , amino acid, or R ₁ and R ₂ together forms CH ₂ ; R ₇ is selected from C ₁ -C ₁₂ alkyl, COR ₈ , alkoxy, or alkyl substituted by (CH ₂ CH ₂ O) _n R ₆ (n=l~3); R ₆ is H, C ₁ -C ₃ alkyl or alkyl substituted by aryl; R ₈ is alkoxy; R ₂ is H, methyl, or R ₂ and R ₁ together form CH ₂ ; R ₃ is H, COR ₇ or amino acid; R ₄ is H, methyl or amino acid; R is H, Cl or F.

The following compounds of formula (I) are particularly preferred:

2-hydroxy-3 , 10-dimethoxy-9-acetoxy- 12-chloro-5 ,8, 13,13 a-tetrahydro-6.H-diben zo[a, gjquinolizine;

2,9-diacetoxy-3 , 10-dimethoxy- 12-chloro-5,8 , 13,13 a-tetrahydro-όϋ-dibenzo [a, gjquinolizine;

2-hydroxy-3 , 10-dimethoxy-9-(2-hydroxy-ethoxy)- 12-chloro-5,8, 13, 13a-tetrahydr o-6H-dibenzo[a, gjquinolizine;

2-hydroxy-3 , 10-dimethoxy-9-ethoxycarbonyloxy- 12-chloro-5 ,8 , 13,13 a-tetrahydr o-6/i-dibenzo[a, g]quinolizine;

2-benzyloxy-3 , 10-dimethoxy-9-phenylalanyloxy- 12-chloro-5 ,8, 13,13 a-tetrahydr o-6/i-dibenzo[a, gjquinolizine;

2,9-diacetoxy-3, 10-dimethoxy-5,8, 13,13a-tetrahydro-6/f-dibenzo[a, gj quinolizine;

2,9-bis- {2-[2-(2-methoxy-ethoxy)-ethoxyJ-acetoxy}-3, 10-dimethoxy- 12-chloro- 5,8,13,13 a-tetrahydro-6H-dibenzo [a, gj quinolizine;

2-hydroxy-3 , 10-dimethoxy-9- {2- [2-(2-methoxy-ethoxy)-ethoxy] -acetoxy } - 12-ch loro-5,8, 13,13a-tetrahydro-6//-dibenzo[a, gjquinolizine;

2,3 ,9, 10-tetrahydroxy- 12-chloro-5 ,8, 13,13 a-tetrahydro-6i/-dibenzo[a, g] quinolizine;

(-)-2,9-diacetoxy-3 , 10-dimethoxy- 12-chloro-5 ,8, 13,13 a-tetrahydro-6H-dibenzo [a, gjquinolizine;

(-)-2, 10-diacetoxy-3 ,9-dimethoxy-5,8, 13,13 a-tetrahydro-6#-dibenzo [a, gj quinolizine;

(-)-2-hydroxy-3 , 10-dimethoxy-9-acetoxy- 12-chloro-5 , 8, 13,13 a-tetrahydro-βH-di benzo[a, gjquinolizine;

2,3-methylenedioxyl-9,10-dimethoxy-12-fluoro-5,8,13,13a-t etrahydro-6H-dibenz o[a, gjquinolizine.

The present invention also related to the method of preparing the compounds of formula (I) and its derivatives.

The compounds of the formula (I) can be prepared by analogy to methods which are well known in the literatures. A preferred method for the preparation of compounds (I) is outlined below: 1. Preparation from formula (II):

(H)

Compound of formula (II) is reacted with compound of formula (III) to prepare compound of formula (I):

R ₃ Y (HI)

Wherein R ₃ is defined as described above, Y is halogen or hydroxy.

(1) Compound of formula (II) is reacted with R ₃ Cl or R ₃ Br. The temperature is in the range of 0 ⁰ C -100 ⁰ C. The reaction is catalysted by appropriate alkali. In detail, in the present of inorganic alkali (for example: NaOH> KOHN CSOHN Ba(OH) ₂ N Mg(OH) ₂ N Ca(OH) ₂ N KHCO ₃ N K ₂ CO ₃ N Na ₂ CO ₃ N Cs ₂ CO ₃ ) or organic alkali (for example: sodium alkoxide, NEt ₃ , N(C ₄ Hg) ₃ , N(C ₃ H ₇ ) ₃ , et al), the mixture was stirred at 0-100 ⁰ C for 2-24 hours to give compound of formula (I). The solvent can be selected in alcohol (for example: methanol, ethanol, isopropanol, C ₄ H ₉ OH, iso-C ₄ H ₉ OH, t-C ₄ H ₉ OH, C ₅ H ₁₁ OH, 1So-C ₅ H ₁₁ OH), the mixture solution of alcohol and water (alcohol: water=5: 9.5-9.5: 0.5, V: V) or other solvent (for example: DMF, CH ₂ Cl ₂ , DMSO, THF, dioxane, pyrolidinylone, acetone and CH ₃ OCH ₂ CH ₂ OCH ₃ ).

(2) Compound of formula (II) is treated with R ₃ COCl, R ₃ CO) ₂ O or R ₃ CO) ₂ O. The reaction carry through in the present of appropriate alkali at 0-100 ⁰ C. In detail, in the present of inorganic alkali (for example: NaOEL KOHN CSOHN Ba(OH) ₂ > Mg(OH) ₂ N Ca(OH) ₂ N KHCO ₃ N K ₂ CO ₃ N Na ₂ CO ₃ N Cs ₂ CO ₃ ) or organic alkali (for example: pyridine, NEt ₃ , N(C ₄ Hg) ₃ , N(C ₃ H ₇ ) ₃ , et al), the mixture was stirred at 0-100 ⁰ C for 2-8 hours to give compound of formula (I). The solvent can be selected in pyridine, DMF, CH ₂ Cl ₂ , DMSO, THF, dioxane and pyrrolidone derivatives. The catalyst such as DMAP is added according the reaction conditions.

(3) Compound of formula (II) is reacted with ClSO ₂ R ₆ , or ClSO ₂ NR ₉ R ₁₀ . The reaction carry through in the present of appropriate alkali at O ⁰ C to room temperature. In detail, in the present of inorganic alkali (for example: NaOHN KOHN CsOH. N Ba(OH) ₂ N Mg(OH) ₂ N Ca(OH) ₂ N KHCO ₃ N K ₂ CO ₃ N Na ₂ CO ₃ N Cs ₂ CO ₃ ) or organic alkali (for example: pyridine, NEt ₃ , N(C ₄ H ₉ ) ₃ , N(C ₃ H ₇ ) ₃ , et al), the mixture was stirred at 0-100 ⁰ C for 2-8 hours to give compound of formula formula (I). The solvent can be selected in pyridine, DMF, CH ₂ Cl ₂ , DMSO, THF, dioxane and pyrrolidone derivatives.

(4) Compound of formula (II) is reacted with N-protected amino acid. The reaction of THPBs with amino acid can be finished through the procedure of esterification. For example, starting from the chloroacetyl derivatives of amino acid to give the desired compound. Another method is treat THPBs and amino acid in the present amino acid catalyst. In detail, the reaction is carried through at O ⁰ C to room temperature to give compound of formula (I). The solvent can be selected in CH ₂ Cl ₂ , DMF or THF. The catalyst can be selected in DCC, CDI, EDCI or other coupled reagent, accompanied by HOBt or DMAP.

(5) The deprotection of N-deprotected amino acid derivatives of THPBs (II) is carried through in the present of acid. In detail, the reaction is carried through at O ⁰ C to room temperature in the present of inorganic acid (for example: HCl, H ₂ SO ₄ , et al) or organic acid (for example: toluenesulfonic acid,, CF ₃ COOH ₅ AcOH, et al). The solvent can be selected in CH ₂ Cl ₂ , THF, et al.

(6) When R ₁ =H, compound of formula (I) was obtained by hydrogenating the

compound of formula (II) (R ₁ =CH ₂ Ph) in the present of catalyst in order to avoid the hydrogenate of halogen in THPBs. In detail, compound of formula (II) is hydrogenated in the present of Raney-Ni at 0-40 ⁰ C for 1-10 hours to give compound of formula (I). The solvent is alcohol (for example: methanol, ethanol, isopropanol, et al) or the mixture solution of alcohol and water.

Compound of formula (II) is given as follow:

A) When R ₂ =R ₄ =CH ₃ and R = Cl, that is 2-benzyloxy-3,10-dimethoxy-9- hydroxy- 12-chloro-5,8, 13 , 13a-tetrahydro-6//-dibenzo[a, g]quinolizine (compound IIA). Intermediate HA is preparation according to the method reported in literature (CN03151464.2), and (-)-IIA is obtained through resolution from IIA (CN03151464.2).

B ) When R ₂ , R ₄ is other substituted groups, the hydroxyl derivatives of THPBs can be obtained by debenzyloxy or demethyl reaction of compound of formula (II) (Ra=R ₄ =CH ₃ ) in the present of BBr ₃ . This compound is esterificated, etherificated, coupled with amino acid or demethylatied to provide the compound of formula (II). The procedure is described above. 2. Preparate from formula (IV):

( IV)

R is Cl, H.

Compound of formula (IV) is treated with compound of formula (III) to preparate formula (I):

R ₁ Y (Or R ₃ Y) (III)

Wherein R ₁ (or R ₃ ) is defmited as described above, Y is halogen or hydroxy.

(1) Compound of formula (IV) is react with R ₁ Cl or R ₁ Br. The procedure is the same as the synthetic procedure described in the reaction of compound of formula (II) with R ₃ Cl or R ₃ Br. The structure of compound of formula (I) is different according the

amount of compound of formula (III) and the activity of the hydroxy of compound of formula (IV).

(2) Compound of formula (IV) is reacted with R ₁ COCl, (RiCO) ₂ O or (R ₃ CO) ₂ O. The procedure is the same as the synthetic procedure described in the reaction of compound of formula (II) with R ₁ COCl, (R ₁ CO) ₂ O or (R ₃ CO) ₂ O. The structure of compound of formula (I) is different according the amount of compound of formula (III) and the activity of the hydroxy of compound of formula (IV).

Compound of formula (IV) is given as follow:

(1) When R is Cl, compound of formula (IV) is given as follow:

Compound of formula (II) was debenzylization with commen method to give compound of formula (VI) (R=Cl). The methods are hydrogenate or hydrolysis by acid. In detail, compound of formula (II) is hydro genated in the present of Raney-Ni at 0-40 ⁰ C for 1-10 hours to give compound of formula (VI) (R=Cl). The solvent is alcohol (for example: methanol, ethanol, isopropanol, et al) or the mixture solution of alcohol and water. Alteratively, compound of formula (II) is heat with acid (for example: HCl, H ₂ SO ₄ , HBr, et al) to debenzylate. The solvent is acid (HCOOH, AcOH, et al) or alcohol (such as ethanol).

(2) When R is H, compound of formula (IV) is given as follow:

Compound of formula (II) (R ₂ =R ₄ =CH ₃ , R=Cl) is hydrogenated in the present of Pd-C under high pressure to give formula (IV) (R = H). In detail,, compound of formula (II) is hydrogenated at 20-60 ⁰ C for 3-24 hours in the present of acid (for example: HC1/H ₂ O, H ₂ SO ₄ VH ₂ O, HBr/H ₂ O, et al) to give compound of formula (IV) (R=H). The solvent is alcohol (for example: methanol, ethanol, isopropanol, et al) or other solvent (DMF, DMSO, THF, et al). 3. Preparation from formula (V):

( V )

Compound of formula (V) is natural product Z-SPD, isolated from plants. Staring from /-SPD, the compound of formula (I) can be provided by esterification, etherification, coupling with amino acid or demethylation. The procedure is described above.

4. The preparation of N-substituted derivatives of formula (I)

The free base of compound of formula (I) is reacted with alkyl halide (for example; CH ₃ I) or substituted halide alkyl (for example; PhCH ₂ Br) at room temperature to 100 ⁰ C, followed by precipitating when cooling, or by separating through column chromatography to give the target product;

5. Preparation from formula (VI):

(VI)

Compound of formula (VI) was reacted with HNO ₂ to give diazo salts, which is react with corresponding reagent to give the compound of formula (I) (R=halogen, cyano).

Compound of formula (VI) can be prepared as follow:

Nitration of compound of formula (I) (R=H) to give nitro derivatives, which is reduced to give compound of formula (VI). The nitro derivatives of compound of formula (I) also can be obtained by cyclization of nitro benzylisoqunoline derivatives.

The physiologically acceptable acid addition salts of formula (I) can be obtained by the conventional methods in the literature. For example, the compound of formula (I) was treated with appropriate acid in appropriate solvent, and the salt can be obtained through evaporating solvents or filtrating.

The compound of formula (I) was treated with appropriate alkali to give physiologically acceptable alkali addition salts.

The pharmacological actions of the compound according to the present invention are detected through the following methods.

1. Dopamine receptor binding studies

The affinities of these compounds on dopamine receptors were evaluated with competitive receptor binding assays (Acta Pharmacol Sin, 1989,10:104 and Acta Pharmacol Sin, 2003, 24(3): 225-229). The Ki is calculated according the inhibition data tested.

/-CSLMS is S-chloroscoulerine mesylate and CSL is chloroscoulerine.

Table 1 Affinities of THPBs for binding to dopamine receptors'*

a: Inhibition(%) data was tested at 1 x 10 ^'5 mol/L

Table 2 Ki values of THPBs for bingding to dopamine receptors

2. 6-OHDA-lesioned rats rotation test

Some of the compounds were evaluated on 6-OHDA-lesioned rats model. In this model, compounds of exmple 7, 44 and 48 exhibit positive effects at 10mg/kg.

3. PCP-induced immobility test in mice Phencyclidine(PCP)-induced immobility test in mice was selected as the model to evaluate the antipsychotic effect of some compounds of the present invention (Br J Pharmacol, 1995, 116: 2531-2537). The dose is selected according the ED ₅₀ of /-CSLMS. Given PCP, immobility times of mice was increased, whereas the active compound can decrease the immobility time. At 20mg/kg (i.g.), the immobility time of compound of example 47 is 54.9±19s, and the immobility time of /-CSLMS is 48.0±27s, which has statistically significant differences (P < 0.05) compared to PCP group(78.1±28s).

The present invention therefore relates to compounds of formula (I) and physiologically acceptable salts.

The present invention therefore relates to a pharmaceutical composition which comprises at least one compound of the formula (I) and/or at least one physiologically acceptable addition salt of (I), together with physiologically acceptable carriers and/or auxiliary substances.

The present invention also relates to a method for treating disorder which respond to influencing by dopamine D ₁ and D ₂ receptor. And a method comprise administering an effective amount of at least one THPBs of the formula (I) and/or at least one physiologically acceptable addition salt of (I) to a subject in need thereof.

The present invention also relates to all the new intermediates described in this invention.

The Preferable Embodiments of the Invention

The following examples serve to explain the invention without limiting it.

The compounds were characterized either via ¹ H NMR or MS.

The compound in formula(II), when R ₂ =R ₄ =CH ₃ , R=Cl, i.e. the intermediate 2-benzyloxy-3 , 10-dimethoxy-9-hydroxy- 12-chloro-5 ,8, 13,13 a-tetrahydro-6H-dibenzo [a, g]quinolizine (compound UA), which is prepared according to the method reported in literature (CN03151464.2), (-)-IIA is obtained through the resolution from HA (CN03151464.2).

Preparation 1 : 2-benzyloxy-3 J0-dimethoxy-9-hydroxy-12-chloro-5,8,13,13a- tetrahydro-6ij-dibenzofa, g] quinolizinefcompound HA) l-(2'-chloro-4'-methoxy-5'-hydroxy)benzyl-6-methoxy-7-benzyl oxy-l ₅ 2,3,4-tetro hydroisoquinolin (compound of formula VII) (103g, 0.235mol) was added methanol (5150ml) and hydrochloric acid to adjust pHl-2. The mixture was then added 37%HCHO (3090ml) and water (2000ml). After stirring for 2 days, the solvent was evaporated and the residue was neutralized with NaHCO ₃ to pH 9. The aqueous was extract with CHCl ₃ . The combined organic layers was dried and concentrated to give desired compound (103g, 97.3%).

Example 1 : 2,9-dihydroxy-3 J0-dimethoxy-12-chloro-5,8 J3,13a-tetrahvdro- 6/7-dibenzo[a, g]quinolizine

Compound IIA (l.Og, 2.2mmol) was dissolved in CH ₃ OH, and Raney-Ni was added. The mixture was stirred for 2~5 hours under hydrogen at normal pressure and room temperature. After filtering the catalyst, the filtrate was concentrated to give the product as pink powder (0.73g, 90.8%). That is chloroscoulerine. mp 136~138 ⁰ C. ¹ HNMR (CDCI ₃ )δ: 2.57-2.70 (3H, m, CH ₂ ), 3.09-3.22 (2H, m, CH ₂ ), 3.21-3.39 (IH, dd, CH ₂ ), 3.45-3.54 (5H, m, CH ₂ , N-CH and CH ₃ OH), 3.85 (3H, s, Ar-OCH ₃ ), 3.88 (3H, s, Ar-OCH ₃ ), 4.20 (IH, d, CH ₂ ), 5.50 (IH, brs, OH), 5.63 (IH, brs, OH), 6.60 (IH, s, ArH), 6.80 (IH, s, ArH), 6.89 (IH, s, ArH).

Example 2: σ.g-dihydroxy-S.lO-dimethoxy-S.S.lS.lSa-tetrahvdro-όH-dibe nzo [a, g]quinolizine hydrochloride

Compound IIA (2.Og, 4.4mmol) was dissolved in CH ₃ OH (200ml), adding

lmol/L hydrochloric acid (5ml) and 10% Pd-C (0.3g). The mixture was hydrogenated under pressure at 50-60 ^° C for 12 hours. After the raw material disappeared detected with TLC, filtering the catalyst, the filtrate was concentrated to give the product as beige powder (1.5g, 93%). That is scoulerine, which can be used as a intermediate for next step, mp 246 ⁰ C. ¹ HNMR (DMSO-d ₆ )δ: 2.46-2.60 (3H, m, CH ₂ ), 3.13 (IH, m, CH ₂ ), 3.14-3.30 (4H, m, CH ₂ or N-CH), 3.74 (3H, s, Ar-OCH ₃ ), 3.76 (3H, s, Ar-OCH ₃ ), 4.03 (IH, d, CH ₂ ), 6.59 (IH, d, ArH), 6.64 (IH, s, ArH), 6.70 (IH, s, ArH), 6.78 (IH, d, ArH).

Example 3 : 2-benzyloxy-3 , 10-dimethoxy-9-benzoyloxy- 12-chloro-5 ,8 , 13,13a- tetrahydro-6H-dibenzo [a, g ^~ | quinolizine

Compound UA (0.5g, l.lmmol) was dissolved in CH ₂ Cl ₂ (30ml), adding benzoyl chloride (0.2g, 0.17ml, 1.4mmol) and triethylamine (0.19ml). The mixture was stirred at room temperature for 5 hours. After the raw material disappeared detected with TLC, the mixture was poured into water, adding lmol/L NaOH. The aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic phase were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=l/5) and recrystallized with ethyl acetate/petroleum ether to give the product as pale yellow powder, mp 170-172 ⁰ C.

Example 4 : 2-hydroxy-3 , 10-dimethoxy-9-benzoyloxy- 12-chloro-5 , 8 , 13 , 13 a- tetrahydro-6f/-dibenzo[a, g]quinolizine

A product obtained in Example 3 (0.183g, 0.33mmol) was add CH ₃ OH (15ml) and Raney-Ni. The mixture was hydrogenated at room temperature for 1 hours. The mixture was filtered, and the filtrate was concentrated to give the product as yellow-green solide (0.16g). The solide was recrystallized with ethyl acetate/petroleum ether to give pale yellow powder (0.041g, 26.7%). mp 162-164 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 2.57-2.71 (3H, m, CH ₂ ), 3.08-3.12(2H, m, CH ₂ ), 3.36-3.58 (3H, m, CH ₂ and N-CH), 3.79 (3H, s, Ar-OCH ₃ ), 3.87(3H, s, Ar-OCH ₃ ), 4.02 (IH, br, CH ₂ ), 5.55 (IH, s, Ar-OH), 6.59 (IH, s, ArH), 6.89 (IH, s, ArH), 6.95 (IH, s, ArH), 7.51-7.56 (2H, m, PhH), 7.65-7.67 (IH, m, PhH), 8.22-8.24 (2H, m, PhH). MS(EI)

m/z: 464 (M-I), 360, 344, 178, 105(base), 77.

Example 5j 2,9-dibenzoyloxy-3, 10-dimethoxy- 12-chloro-5,8, 13.13a- tetrahydro-6H ^" -dibenzo[ ^~ a, g ^~ |quinolizine

A product obtained in Example 1 (0.15g, 0.41mmol) was suspend on CH ₂ Cl ₂ (20ml), adding benzoyl chloride (0.22ml) and triethylamine (0.26ml). The mixture was stirred at room temperature for 7 hours. Then the reaction was diluted with CH ₂ Cl ₂ (10ml), followed by adding 0.5mol/L ήtf NaOH. The aqueous phase was extracted two times with CH ₂ Cl ₂ . The combined organic layers were washed with water, brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=l/4) to give pale yellow powder (0.18g, 76.2%). The analytic sample was recrystallized by ethyl acetate/petroleum ether, mp 152-154 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 2.61-2.76 (3H, m, CH ₂ ), 3.14(2H, m, CH ₂ ), 3.36-3.41 (2H, m, CH ₂ and N-CH), 3.61 (IH, m, CH ₂ ), 3.78 (3H, s, Ar-OCH ₃ ), 3.80(3H, s, Ar-OCH ₃ ), 4.09 (IH, br, CH ₂ ), 6.75 (IH, s, ArH), 6.95 (IH ₃ s, ArH), 7.11 (IH, s, ArH), 7.50-7.56 (4H, m, PhH), 7.62-7.67 (2H, m, PhH), 8.23-8.25 (4H, m, PhH).

Example 6 : 2-benzyloxy-3 , 10-dimethoxy-9-acetoxy- 12-chloro-5,8, 13 J 3a- tetrahydro-6H-dibenzo [a, g ^" |quinolizine

Compound HA (0.5g, 1.1ml) was dissolved in pyridine (10ml), adding acetyl anhydride (ImI). The mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated to small volume and poured into water, adjusting to pH 8 with saturated NaHCO ₃ . The aqueous phase was extracted three times with CH ₂ Cl ₂ . The combined organic layers were washed with water, brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was discolored by activated carbon and recrystallized with CH ₂ Cl ₂ /hexane to give product (0.246g, 45%). mp 150-152 ⁰ C. ¹ HNMR (CDCl ₃ )δ:2.33 (3H, s, COCH ₃ ), 2.49-2.71 (3H, m, CH ₂ ), 3.12~3.15(3H, m, CH ₂ ), 3.39-3.52 (2H, m, CH ₂ and N-CH), 3.80 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 3.98 (IH, d ₅ CH ₂ ), 5.16 (2H, q, Ph-CH ₂ ), 6.63 (IH, s, ArH), 6.76 (IH, s, ArH), 6.90 (IH, s, AiH), 7.26-7.32 (IH, m, PhH), 7.35-7.39 (2H, t, PhH), 7.45-7.47 (2H, d, PhH).

Example 7 : 2-hvdroxy-3.10-dimethoxy-9-acetoxy- 12-chloro-5.8 , 13,13a- tetrahvdro-6/i ^" -dibenzo[ ^~ a, glquinolizine

A product obtained in Example 6 (0.07Og, 0.14mmol) was add CH ₃ OH (15ml) and Raney-Ni. The mixture was hydrogenated at room temperature for 2 hours. The mixture was filtered, and the filtrate was concentrated to give the product as pale yellow oil. The oil was recrystallized with ethyl acetate/petroleum ether (1/3) to give pale yellow powder (0.022g, 38.4%). mp 191-192 ⁰ C. Anal: Cacul: C 62.45%, H 5.49%, N3.47%; test: C 62.19%, H 5.41%, N3.22%. ¹ HNMR (CDCl ₃ )δ: 2.34 (3H, s, COCH ₃ ), 2.58-2.69 (3H, m, CH ₂ ), 3.10~3.15(2H, m, CH ₂ ), 3.33-3.43 (2H, m, CH ₂ and N-CH), 3.52-3.56 (IH, brd, CH ₂ ), 3.80 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 3.99 (IH ₃ d, CH ₂ ), 5.54 (IH, s, Ar-OH), 6.59 (IH, s, ArH), 6.87 (IH, s, ArH), 6.91 (IH, S ₅ ArH). MS(EI) m/z: 405 (M+2), 403 (M ⁺ ), 360, 344(S% 186, 149, 91.

Example 8 : 2,9-diacetoxy-3, 10-dimethoxy- 12-chloro-5,8, 13,13a-tetrahydro- 6H-dibenzo[a, glquinolizine acetate

A product obtained in Example 1 (0.2g, 0.55mmol) was dissolved in pyridine (10ml), adding acetyl anhydride (ImI). The mixture was stirred at room temperature overnight. The mixture was concentrated to small volume under reduced pressure. The solution was adding water (5ml) slowly with stirring. The solid precipated was collected by filtration and dryed at 50 ⁰ C to give gray powder (0.151g, 61.3 %). mp 205-206 ⁰ C. ¹ HNMR (CDCl ₃ )S: 2.34 (6H, 2s, 2 ^χ COCH ₃ ), 2.60-2.75 (3H, m, CH ₂ ), 3.11-3.16(2H, m, CH ₂ ), 3.28-3.42 (2H, m, CH ₂ ), 3.53-3.57 (IH, m, CH ₂ and N-CH), 3.80 (3H, s, Ar-OCH ₃ ), 3.82(3H, s, Ar-OCH ₃ ), 3.99 (IH, d, CH ₂ ), 6.70 (IH, s, ArH), 6.90 (IH, s, ArH), 6.97 (IH, s, ArH). MS(EI) m/z: 445 (M ⁺ ), 444(M-I), 386(base), 184, 176, 77.

Example 9j 2-benzyloxy-3 , 1 O-dimethoxy-9-cmnamoyloxy- 12-chloro-

5.8,13,13 a-tetrahvdro-6H-dibenzo [a, gi quinolizine

Compound HA (0.3 g, 0.66mmol) was dissolved in CH ₂ Cl ₂ (20ml), adding cinnamyl chloride (0.132g, 0.79mmol) and triethylamine (0.11ml). The desired product was obtained following the synthetic procedure described in Example 3. The crude solid was recrystallized with CH ₂ Cl ₂ /hexane to give beige product (0.206g,

53.3%). mp 198-200 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 2.86-3.01 (3H, m, CH ₂ ), 3.41~3.57(3H, m, CH ₂ and N-CH), 3.73-3.79 (2H, m, CH ₂ ), 4.14 (3H, s, Ar-OCH ₃ ), 4.21 (3H, s, Ar-OCH ₃ ), 4.35 (IH, d, CH ₂ ), 5.50 (2H, q, PhCH ₂ ), 6.96 (IH, s, ArH), 7.01 (IH, d, CH-R), 7.12 (IH, s, ArH), 7.59 (IH, s, ArH), 7.63-7.82 (8H, m, PhH), 7.92-7.95 (2H, m, PhH), 8.23 (IH, d, CH=R).

Example 10 : 2-hydroxy-3 , 1 O-dimethoxy-9-f 3 -phenyl-propionyloxyV 12- chloro-5 , 8 , 13 , 13 a-tetrahydro-6H-dibenzo [a, g] quinolizine

A product obtained in Example 9 (0.06g, O.lOmmol) suspend on CH ₃ OH (10ml), adding Raney-Ni. The mixture was hydrogenated at room temperature for 4 hours. The mixture was filtered, and the filtrate was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=l/4) to give white powder (0.034g, 51.8%). ¹ HNMR (CDCl ₃ )δ: 2.47-2.68 (3H, m, CH ₂ ), 2.92-3.12 (6H, m, CH ₂ ), 3.19-3.24 (IH, m, CH ₂ ), 3.29-3.36 (IH, dd, CH ₂ ), 3.46-3.51 (IH, dd, CH ₂ and N-CH), 3.76 (3H, s, Ar-OCH ₃ ), 3.78 (IH, d, CH ₂ ), 3.88 (3H, s, Ar-OCH ₃ ), 5.51 (IH, s, Ar-OH), 6.59 (IH, s, ArH), 6.86 (IH, s, ArH), 6.88 (IH, s, ArH), 7.21-7.35 (5H, m, PhH).

Example 11 : 2.,9-dicirmamoyloxy-3 JO-dimethoxy-^-chloro-S^JSJSa- tetrahydro-ό.H-dibenzo [a, g] quinolizine

A product obtained in Example 1 (0.2g, 0.55mmol) suspend on CH ₂ Cl ₂ (20ml), adding cinnamyl chloride (0.28g, 1.68mmol) and triethylamine (0.24ml). The mixture was stirred at room temperature for 7 hours. Then the mixture was poured into water, adjusting to pH 8 with saturated NaHCO ₃ . The aqueous phase was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography and recrystallized with ethyl acetate/petroleum ether to give pale yellow powder (0.057g, 16.6%). mp 240-242 ⁰ C. ¹ HNMR (DMSO-d ₆ )δ: 2.44-2.56 (IH, m, CH ₂ ), 2.73-2.78 (IH, m, CH ₂ ), 3.01-3.16 (2H, m, CH ₂ ), 3.41 (3H, s, CH ₂ ), 3.54 (IH, dd, N-CH), 3.78 (3H, s, Ar-OCH ₃ ), 3.80 (3H, s, Ar-OCH ₃ ), 4.03 (IH, d, CH ₂ ), 6.84 (IH, d, CH-R), 6.87 (IH, s, ArH), 6.87 (IH, d, CH=R), 7.13 (IH, s, ArH), 7.15 (IH, s, ArH), 7.46-7.49 (6H, m, PhH), 7.76-7.83 (4H,

m, PhH), 7.85 (IH, d, CH=R) ₃ 7.89 (IH ₅ d, CH=R).

Example 12 : 2-benzyloxy-3 , 10-dimethoxy-9-propyloxy- 12-chloro-5 , 8 , 13 J 3 a- tetrahydro-6H-dibenzo|ra, giquinolizine

Compound HA (0.3g, 0.66mmol) was dissolved in ethanol, adding lmol/LNaOH (5ml) and propyl bromide (ImI). The mixture was heating to 50-60 ⁰ C. When the reaction was finished, the mixture was concentrated to small volume followed by adding water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=l/5) to give desired product (O.lOg, 30.5%). mp 118-120 °C. ¹ HNMR (CDCl ₃ )δ: 1.03 (3H, t, CH ₃ ), 1.79 (2H, q, CH ₂ ), 2.66-2.71 (3H, m, CH ₂ ), 3.16-3.21 (3H, m, CH ₂ ), 3.46-3.50 (2H ₅ m, CH ₂ and N-CH), 3.82 (3H, s, Ar-OCH ₃ ), 3.89(3H, s, Ar-OCH ₃ ), 3.93-3.97 (2H, t, OCH ₂ ), 4.22 (IH, d, CH ₂ ), 5.17 (2H, q, PhCH ₂ ), 6.64 (IH ₅ s, ArH) ₃ 6.79 (IH ₃ S ₃ ArH) ₃ 6.84 (IH, s, ArH), 7.26-7.32 (IH ₅ m, PhH) ₃ 7.36-7.39 (2H ₅ t, PhH) ₃ 7.46-7.48 (2H ₅ d, PhH).

Example 13 : 2-hydroxy-3 , 10-dimethoxy-9-propyloxy- 12-chloro-5 ,8 , 13,13a- tetrahydro-6H-dibenzo [a, g] quinolizine

A product obtained in Example 12 (0.045g, 0.09mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example I ₅ 4, 7 or 10. The crude product was purified by silica chromatography to give the product (0.026g, 70.7%). ¹ HNMR (CDCl ₃ )δ: 1.03 (3H ₅ 1, CH ₃ ), 1.79 (2H, q, CH ₂ ), 2.64-2.71 (3H, m, CH ₂ ), 3.19-3.53 (5H, m, CH ₂ and N-CH), 3.82 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 3.93-3.97 (2H, t, OCH ₂ ), 4.24 (IH ₅ d, CH ₂ ), 5.54 (IH, brs, Ar-OH), 6.60 (IH, s, ArH) ₅ 6.85 (IH ₅ s ₅ ArH) ₅ 6.88 (IH, s, ArH).

Example 14 : 2-benzyloxy-3 , 10-dimethoxy-9-methanesulfonyloxy- 12-chloro- 5,8,13, 13a-tetrahydro-6ij ^" -dibenzora, g]quinolizine

Compound HA (0.2g, 0:44mmol) was dissolved in pyridine (1OmI) ₅ adding methanosulfonyl chloride (0.17ml) with ice bath and stirring overnight. The mixture was concentrated to small volume under reduced pressure. The residual solution was

add CH ₂ Cl ₂ , following filtration. The filtrate was washed with water, saturated NaHCO ₃ and brine. The solvent was dried over Na ₂ SO ₄ , filtered, and evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=l/3) to give desired product (0.086g, 36.7%). The analytic sample was recrystallized by ethyl acetate/petroleum ether. ¹ HNMR (CDCl ₃ )δ: 2.46-2.69 (3H, m, CH ₂ ), 3.02-3.20 (3H, m, CH ₂ ), 3.33 (3 H, s, SO ₂ CH ₃ ), 3.49-3.54 (IH, dd, CH ₂ and N-CH), 3.62 (IH, d, CH ₂ ), 3.87 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.23 (IH, d, CH ₂ ), 5.16 (2H, q, PhCH ₂ ), 6.63 (IH, s, ArH), 6.75 (IH, s, ArH), 6.92 (IH, S ₅ ArH), 7.29-7.39 (3H, m, PhH), 7.45-7.47 (2H, m, PhH).

Example 15 :2-hydroxy-3 , 1 O-dimethoxy-9-methanesulfonyloxy- 12-chloro-5 ,8.13 , 13 a-tetrahydro-6H-dibenzo [a, g] quinolizine

A product obtained in Example 14 (0.035g, 0.07mmol) was hydrogenated in the present of Raney-Ni. The desired product as pale yellow powder (0.027g, 92.9%) was obtained following the synthetic procedure described in Example 1, 4 or 7. ¹ HNMR (CDCl ₃ )δ: 2.58-2.70 (3H, m, CH ₂ ), 3.04-3.24, 3.38-3.39 (3H, m, CH ₂ ), 3.34 (3H, s, SO ₂ CH ₃ ), 3.54-3.66 (2H, m, CH ₂ and N-CH), 3.87 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.25 (IH, d, CH ₂ ), 5.52 (IH, brs, Ar-OH), 6.60 (IH, s, ArH), 6.87 (IH, s, ArH), 6.93 (IH, s, ArH)-MS(EI) m/z: 439 (M ⁺ ), 360(base), 344, 183, 176, 77.

Example 16: 2-benzyloxy-3, 10-dimethoxy-9-(2-hydroxy-ethoxy)-12-chloro- 5,8,13,13 a-tetrahydro-6/i-dibenzo Fa, R] quinolizine

Compound HA (0.2g, 044mmol), 1-chloroethanol (0.16ml), K ₂ CO ₃ (0.38g, 2.8mmol), DMF (10ml) was mixed and heat to 100 ⁰ C for 6 hours. The mixture was concentrated to remove DMF and poured into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether/methanol) and recrystallized with ethyl acetate to give pale yellow crystal (0.157g, 71.5%). mp 154 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 2.47-2.70 (3H, m, CH ₂ ), 2.82 (IH, brs, OH), 3.11-3.21 (3H, m, CH ₂ ), 3.44-3.50 (2H, m, CH ₂ and N-CH), 3.84 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 3.84-3.88 (2H, br _; OCH ₂ ), 3.97-4.01 (IH, m,

OCH ₂ ), 4.11-4.16 (IH, m, OCH ₂ ), 4.22 (IH, d, CH ₂ ), 5.16 (2H, q, PhCH ₂ ), 6.63 (IH, s, ArH), 6.78 (IH, s, ArH), 6.86 (IH, s, ArH), 7.28-7.32 (IH, m, PhH), 7.35-7.39 (2H, m, PhH), 7.45-7.48 (2H, m, PhH).

Example 17 : 2-hydroxy-3 , 10-dimethoxy-9-(2-hvdroxy-ethoxy> 12-chloro- 5,8,13,13 a-tetrahydro-6 H-dibenzo [a, g] quinolizine

A product obtained in Example 16 (0.08g, O.lόmmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow powder (0.013 g, 19.9%). mp 184 ⁰ C ¹ HNMR (DMSO-d ₆ )δ: 2.28-2.56 (3H, m, CH ₂ ), 2.71-2.88 (2H, m, CH ₂ ), 3.04-3.31 (3H, m, CH ₂ and N-CH), 3.61(2H, t, OCH ₂ ), 3.73 (3H, s, Ar-OCH ₃ ), 3.78 (3H, s, Ar-OCH ₃ ), 3.94 (2H, m, OCH ₂ ), 4.18 (IH, d, CH ₂ ), 6.64 (IH, s, ArH), 6.72 (IH, S ₅ ArH), 7.03 (IH, s, ArH).

Example 18: 2-benzyloxy-3 J0-dimethoxy-9-[2-(2-hvdroxy-ethoxy)-ethoxy]- 12-chloro-5,8J3, 13a-tetrahydro-6H-dibenzo| ^" a. g]quinolizine

Compound HA (0.5g, l.lmmol), 1-chloroethylglycol (0.45g, 3.6mmol), K ₂ CO ₃ (0.3 Ig, 2.2mmol), DMF (15ml) was mixed and heat to 100 ⁰ C for 20 hours. After filtering K ₂ CO ₃ , the mixture was concentrated to remove DMF, followed by pouring into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether) to give yellow needle (0.416g, 69.6%). The analytic sample was recrystallized with ethyl acetate/petroleum ether, mp 122 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 2.44-2.69 (3H, m, CH ₂ ), 3.07-3.23 (3H, m, CH ₂ ), 3.37-3.51 (3H, m, CH ₂ and N-CH), 3.60-3.71 (5H, m, CH ₂ )3.82 (3H, s, Ar-OCH ₃ ), 3.87(3H, s, Ar-OCH ₃ ), 4.20-4.24 (2H, m, OCH ₂ ), 4.39 (IH, d, CH ₂ ), 5.16 (2H, q, PhCH ₂ ), 6.62 (IH, s, ArH), 6.77 (IH, s, ArH), 6.83 (IH, s, ArH), 7.29-7.31 (IH, m, PhH), 7.34-7.39 (2H, m, PhH), 7.45-7.47 (2H, m, PhH). MS(EI) m/z: 539 (M-I), 448, 283, 91(base).

Example 19: 2-hydroχy-3 J0-dimethoxy-9-r2-f2-hydroxy-ethoxyVethoxy]-

12-chloro-5,8,13, 13a-tetrahydro-6if-dibenzo[ ^" a, glquinolizine

A product obtained in Example 18 (0.116g, 0.21mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether/methanol) to give yellow solid (0.035g, 36.2%). ¹ HNMR (CDCl ₃ )δ: 2.61-2.68 (3H, m, CH ₂ ), 3.18-3.70 (HH ₅ m, CH ₂ and N-CH), 3.81 (3H, s, Ar-OCH ₃ ), 3.84(3H, s, Ar-OCH ₃ ), 4.21 (2H, m, OCH ₂ ), 4.40 (IH, d ₅ CH ₂ ), 6.57 (IH, s ₅ ArH), 6.83 (IH, s, ArH), 6.85 (IH, s, ArH).

Example 20 : 2-benzyloxy-3 , 10-dirnethoxy-9-ethoxycarbonyloxy- 12-chloro- 5,8,13,13 a-tetrahvdro-6ij-dibenzo [a, g] quinolizine

Compound HA (0.5g, l.lmmol), ClCOOC ₂ H ₅ (2.2mmol), K ₂ CO ₃ (0.46g, 3.3mmol), DMF (10ml) was mixed and heat to 80 ⁰ C. When the reaction finished, the mixture was concentrated to remove DMF. The residue was poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow powder (0.195g, 33.6%). mp 128 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 1.39 (3H, t, CH ₃ ), 2.50-2.68 (3H, m, CH ₂ ), 3.12-3.19 (3H, m, CH ₂ ), 3.43-3.50 (2H, m, CH ₂ and N-CH), 3.82 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.07 (IH, d, CH ₂ ), 4.32 (2H, q, CH ₂ ), 5.16 (2H, q, PhCH ₂ ), 6.63 (IH, s, ArH), 6.76 (IH, s, ArH), 6.90 (IH, s, ArH), 7.28-7.32 (IH, m, PhH), 7.35-7.39 (2H, m, PhH), 7.45-7.48 (2H, m, PhH).

Example 21 : 2-hydroxy-3,10-dimethoxy-9-ethoxycarbonyloxy-12-chloro- 5,8,13,13 a-tetrahvdro-6H-dibenzo [a, g] quinolizine

A product obtained in Example 20 (0.09g, 0.17mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was recrystallized with CH ₂ Cl ₂ /hexane to give pink solid (0.044g, 59.0%). mp 169-170 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 1.39 (3H, t, CH ₃ ), 2.59-2.68 (3H, m, CH ₂ ), 3.10-3.16 (2H, m, CH ₂ ), 3.33-3.56 (3H, m, CH ₂ and N-CH), 3.82 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.08 (IH, d, CH ₂ ), 4.32 (2H, q, CH ₂ ), 5.52 (IH, brs, Ar-OH), 6.60 (IH, s, ArH), 6.87

(IH, S ₅ ArH), 6.91 (IH, s, ArH). MS(EI) m/z: 432 (M-I), 344(base), 183, 176, 91.

Example 22 : 2-benzyloxy-3 , 10-dimethoxy-9-(N-t-Boc-phenylalanyloxy)- 12-chloro-5,8, 13, 13a-tetrahydro-6H-dibenzora, glquinolizine

Method A:

Compound HA (0.5g, l.lmmol) was dissolved in CH ₂ Cl ₂ (20ml), adding t-Boc-phenylanine (0.88g, 3.3mmol) and DCC (0.91g, 4.4mmol). The mixture was stirred at room temperature for 6 hours, then cooled in refrigeratory. Afer filtered, the filtrate was washed with cool citrate buffer, cool saturated NaHCO ₃ and cool water. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica chromatography to give pale yellow solid (0.722g, 93.3%). mp 140~141 °C. ¹ HNMR (CDCl ₃ )δ: 1.41 (9H, 2xs, 3xCH ₃ ), 2.46-2.68 (3H, m, CH ₂ ), 3.03-3.19 (4H, m, CH ₂ ), 3.28-3.49 (3H, m, CH ₂ and N-CH), 3.79 (3H, d, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.85 (IH, m, CH ₂ ), 4.98 (IH, m, COCH), 5.17 (2H, q, PhCH ₂ ), 6.63 (IH, s, ArH), 6.76 (IH ₅ s, ArH), 6.90 (IH ₅ s, ArH), 7.28-7.40 (8H, m, PhH), 7.46-7.48 (2H, m, PhH). MS(EI) m/z: 698 (M ⁺ ), 641, 450, 434(base), 360, 91.

Method B: t-Boc-phenylanine (0.177g, 0.67mmol) and CDI (0.227g, 1.4mmol) was dissolved in dry THF (10ml) and stirred at room temperature for 30 minitues. Then the solution of compound HA (0.3g, 0.66mmoi) in THF (10ml) was added and stirred for one day. The mixture was evaporated under reduced pressure and purified by Al ₂ O ₃ chromatography to give beige solid (0.114g, 24.6%).

Example 23: 2-benzyloxy-3,10-dimethoxy-9-phenylalanyloxy-12-chloro-5,8, 13,13 a-tetrahydro-όH-dibenzoFa, glquinolizine

A product obtained in Example 22 (0.209g, 0.30mmol) was stirred with 10% CF ₃ COOH in CH ₂ Cl ₂ at room temperature for 2 hours. Then the mixture was concentrated and added water, adjusting to pH 8 with saturated NaHCO ₃ . The aqueous phase was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give desired product

(0.026g, 14.5%). ¹ HNMR (CDCl ₃ )δ: 2.46-2.69 (3H ₅ m, CH ₂ ), 2.96-3.49 (7H, m, CH ₂ and N-CH), 3.79 (3H, d, Ar-OCH ₃ ), 3.85 (IH, s, CH ₂ ), 3.88(3H, s, Ar-OCH ₃ ), 4.03-4.08(1H ₅ m, COCH), 5.17 (2H, q, PhCH ₂ ), 6.64 (IH, S ₅ ArH), 6.77 (IH ₅ s, ArH) ₅ 6.91 (IH, s, ArH), 7.28-7.48 (1OH, m, PhH).

Example 24 : 2-hydroxy-3 , 1 O-dimethoxy-9-flSf-t-Boc-phenylalanyloxyV 12- chloro-5 , 8,13,13 a-tetrahydro-6H-dibenzo [a. gl quinolizine

A product obtained in Example 22 (0.166g, 0.24mmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7 to give pink powder (0.063g, 43.6%0. mp 110 ^° C. ¹ HNMR (CDCl ₃ )δ: 1.41 (9H, 2 ^χ s ₅ 3xCH ₃ ) ₅ 2.52-2.68 (3H ₅ m ₅ CH ₂ ), 3.02-3.19 (3H, m, CH ₂ ), 3.30-3.33 (3H, m ₅ CH ₂ ), 3.49-3.53 (IH, m, CH ₂ and N-CH), 3.79 (3H, d, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.86 (IH ₅ m, CH ₂ ), 4.98 (IH ₅ m ₅ COCH) ₅ 6.59 (IH ₅ s, ArH) ₅ 6.87 (IH, s, ArH), 6.90 (IH, s, ArH) ₅ 7.27-7.37 (5H ₅ m, PhH).

Example 25 : 2-hydroxy-3 , 10-dimethoxy-9-phenylalanyloxy- 12-chloro- 5,8,13,13 a-tetrahydro-όH-dibenzo [a, g] quinolizine

A product obtained in Example 24 was treat with 10% CF ₃ COOH in CH ₂ Cl ₂ . The desired product was obtained following the synthetic procedure described in Example 23.

Example 26 : 2-benzyloxy-3 , 10-dimethoxy-g-fN-t-Boc-glycyloxy)- 12-chloro- 5,8,13,13 a-tetrahy dro-6i/-dibenzo [a, gl quinolizine

Method A:

Compound HA (0.25g, 0.55mmol) was dissolved in CH ₂ Cl ₂ (20ml), adding t-Boc-glycine (0.214g ₅ 1.22mmol) and DCC (0.407g, 1.98mmol). The mixture was stirred at room temperature for 24 hours, then cooled in refrigeratory. Afer filtered, the filtrate was washed with cool citrate buffer, cool saturated NaHCO ₃ and cool water. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The crude product was dissolved with ethyl acetate and filtered. The filtrate was recrystallized with ethyl acetate to give pale yellow solid (0.238g, 70.8%). mp 160 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 1.46 (9H, S ₅ 3*CH ₃ ) ₅ 2.49-2.69 (3H,

m, CH ₂ ), 3.04-3.20 (3H, m, CH ₂ ), 3.35-3.50 (2H, m, CH ₂ and N-CH), 3.79 (3H, s, Ai-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 3.97 (IH, d, CH ₂ ), 4.21 (2H ₃ d, COCH ₂ ), 5.08 (IH, brs, NH), 5.16 (IH, q, PhCH ₂ ), 6.63 (IH, s, ArH) ₅ 6.76 (IH, s, ArH), 6.89 (IH, s, ArH), 129-132 (IH, m, PhH), 7.35-7.39 (2H, m, PhH), 7.45-7.48 (2H, m, PhH).

Method B: t-Boc-glycine (0.236g, 1.35mmol) was ) was dissolved in dry CH ₂ Cl ₂ (10ml), adding CDI (0.32g, 1.98mmol). The mixtured was stirred at room temperature for 1 hours and added the solution of compound HA (0.25g, 0.55mmol) in CH ₂ Cl ₂ (10ml). The mixture was stirred for 24 hours, followed evaporating under reduced pressure and purifing by Al ₂ O ₃ chromatography to give desired product.

Method C: t-Boc-glycine (0.29g, 1.66mmol), EDCI (0.44g, 2.2mmol) and HOBt (0.3g, 2.2mmol) was dissolved in THF (10ml) and stirred at room temperature for 30 minitues. After adding the solution of compound HA (0.5g, l.lmmol) in THF (10ml), the mixture was stirred at room temperature for 24 hours. Then the mixture was evaporated under reduced pressure and dissolved in CH ₂ Cl ₂ . The solution was washed with saturated NH ₄ Cl, saturated NaHCO ₃ and brine, then dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give foam solid (0.476g, 70.8 %).

Example 27 : 2-benzyloxy-3.10-dimethoxy-9-glycyloxy- 12-chloro-5 ,8 J 3,13a- tetrahydro-6#-dibenzo Fa, gl quinolizine

Method A:

A product obtained in Example 26 (O.lg, 0.16mmol) was treat with 10 % CF ₃ COOH in CH ₂ Cl ₂ . The mixture was evaporated under reduced pressure to give desired product.

Method B:

A product obtained in Example 26 (O.lg, O.lδmmol) was dissolved CH ₂ Cl ₂ , followed by treating with p-methylphenylsulfonic acid (0.055g). The mixture was stirred at room temperature, followed by pouring into water. The aqueous phase was adjust to pH 8 with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The combined

organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give desired product.

Example 28 : 2-hydroxy-3 , 10-dimethoxy-9-(N-t-Boc-glycyloxyV 12-chloro- 5,8,13,13 a-tetrahydro-όH-dibenzo [a, g] quinolizine

A product obtained in Example 26 (O.lg, O.lόmmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give yellow powder (0.02 Ig, 24.6%). mp 213-214 ⁰ C. ¹ HNMR (CDCl ₃ + CD ₃ OD)δ: 1.41 (9H, s, 3xCH ₃ ), 2.48-2.66 (3H, m, CH ₂ ), 2.97-3.18 (2H, m, CH ₂ ), 3.34-3.47 (3H ₅ m, CH ₂ and N-CH), 3.74 (3H, s, Ar-OCH ₃ ), 3.78(3H, s, Ar-OCH ₃ ), 3.99 (IH, d, CH ₂ ), 4.04 (2H, s, COCH ₂ ), 5.08 (IH, brs, NH), 6.59 (IH, s, ArH), 6.73 (IH, s, ArH), 6.97 (IH, s, ArH), 7.69 (1H ₃ S ₅ Ar-OH).

Example 29: 2-hvdroxy-3,10-dimethoxy-9-glycyloxy-12-chloro-5,8,13,13a- tetrahydro-6H-dibenzo[a, g]quinolizine

A product obtained in Example 28 was treat with 10% CF ₃ COOH in CH ₂ Cl ₂ . The desired product was obtained following the synthetic procedure described in Example 23.

Example 30: 2.9-bis-(N-t-Boc-valyloxy)-3 , 10-dimethoxy- 12-chloro-

5,8,13,13 a-tetrahydro-6H-dibenzo [a, gi quinolizine

A product obtained in Example 1 (O.lg, 0.28mmol), t-Boc-valine (0.32g, 1.47mmol), DCC (0.23g, l.lmmol), DMAP (0.034g, 0.28mmol) and CH ₂ Cl ₂ (10ml) was mixed and stirred at room temperature for 24 hours. The mixture was then cooled in refrigeratory. Afer filtered, the filtrate was washed with cool citrate buffer, cool saturated NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow solid (0.146g ₅ 69.5%). mp 108-110 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 1.04 (6H ₅ d, 2 ^χ CH ₃ ), 1.10 (6H, q, 2 ^χ CH ₃ ), 1.47 (18H, d, 6 ^χ CH ₃ ), 2.33-2.43 (2H, m, CH ₂ ), 2.61-2.74 (3H, m, CH ₂ ), 3.13-3.17 (2H, m, CH ₂ and CH), 3.28-3.56 (3H, m, CH ₂ and N-CH), 3.77 (3H, s,

Ar-OCH ₃ ), 3.79(3H, s, Ar-OCH ₃ ), 4.03 (IH, d, CH ₂ ), 4.52 (2H, m, COCH) ₃ 6.69 (IH, s, ArH), 6.89 (IH, S ₅ ArH) ₅ 6.98 (IH, d, ArH).

Example 31: 2.9-divalyloxy-3.10-dimethoxy-12-chloro-5.8.13J3a- tetrahvdro-όH-dibenzo [a, g] quinolizine

A product obtained in Example 30 (O.lg, 0.13mmol) was treat with 10 % CF ₃ COOH in CH ₂ Cl ₂ . The desired product was obtained following the synthetic procedure described in Example 23.

Example 32 : f-)-2.10-bis-(N-t-Boc-valyloxyV3.9-dimethoxy-5.8.13 , 13a- tetrahydro-6H-dibenzo [a, g] quinolizine

/-SPD (0.09g, 0.27mmol), t-Boc-valine (0.144g, 0.66mmol), DCC (0.189g, 0.92mmol), DMAP (0.049g, 0.4mmol) and CH ₂ Cl ₂ (10ml) was mixed and stirred at room temperature for 48 hours. The mixture was then cooled in refrigeratory. Afer filtered, the filtrate was washed with cool citrate buffer, cool saturated NaHCO ₃ and brine. The organic layer was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow solid (0.115g, 57.6%). ¹ HNMR (CDCl ₃ )δ: 1.02-1.03 (6H ₅ d, 2*CH ₃ ) ₅ 1.08-1.11 (6H, q, 2 ^χ CH ₃ ), 1.46-1.48 (18H, d, 6xCH ₃ ), 2.36-2.42 (2H, m, CH ₂ ), 2.63-2.75 (2H ₅ m, CH ₂ ), 2.83-2.89 (IH ₅ m, CH ₂ ), 3.14-3.24 (3H, m, CH ₂ and CH), 3.53-3.57 (2H ₅ m, CH ₂ and N-CH) ₅ 3.78 (3H, s, Ar-OCH ₃ ), 3.79(3H, s, Ar-OCH ₃ ), 4.18 (IH, d, CH ₂ ), 4.52 (IH, d, COCH), 4.54 (IH ₅ d, COCH) ₅ 6.70 (IH ₅ s, ArH), 6.91 (3H, m, ArH).

Example 33 : (-V2.10-divalyloxy-3.9-dimethoxy-5.8.13.13 a-tetrahvdro-6/f- dibenzoFa, g] quinolizine

A product obtained in Example 32 (O.lg, 0.14mmol) was treat with 10 % CF ₃ COOH in CH ₂ Cl ₂ . The desired product was obtained following the synthetic procedure described in Example 23.

Example 34: 2,9-diacetoxy-3J0-dimethoxy-5.8J3J3a-tetrahydiO-6iJ- dibenzofa, g] quinolizine

A product obtained in Example 2 (O.lg, 0.27ml) was dissolved in pyridine (10ml), adding acetyl anhydride (0.5ml). The mixture was stirred at room temperature

for 2 hours. The mixture was concentrated under reduced pressure and added water. Then the aqueous phase was adjust to pH 8 with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to give pale desired product (0.073g, 64.6%). mp 212-214 ⁰ C. ¹ HNMR (CDCl ₃ )δ: 2.33 (3H, s, COCH ₃ ), 2.34 (3H, s, COCH ₃ ), 2.63-2.75 (3H, m, CH ₂ ), 3.13~3.20(3H, m, CH ₂ ), 3.41-3.56 (2H, m, CH ₂ and N-CH), 3.81 (3H, s, Ar-OCH ₃ ), 3.82(3H, s, Ar-OCH ₃ ), 4.02 (IH, d, CH ₂ ), 6.70 (IH, s, ArH), 6.83 (IH ₅ d, ArH), 6.92 (IH, s, ArH), 7.00 (IH, S ₅ ArH).

Example 35 : 2-benzyloxy-3 , 10-dimethoxy-9- (2-[2-(2-hvdroxy-ethoxy)- ethoxy] -ethoxy } - 12-chloro-5 ,8 , 13,13 a-tetrahydro-6/f-dibenzo[a, giquinolizine

Compound HA (0.5g, l.lmmol), Cl(CH ₂ CH ₂ O) ₃ H (0.6Ig ₅ 3.6mmol), K ₂ CO ₃ (0.3Ig ₅ 2.2mmol) and DMF (15ml) was mixed and heat to 100 ⁰ C for 20 hours. After filtering K ₂ Cθ ₃ , the mixture was concentrated to remove DMF, followed by pouring into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether) to give yellow powder (0.418g, 65.1%). The analytic sample was recrystallized with ethyl acetate/petroleum ether. ¹ HNMR (CDCl ₃ )δ: 2.44-2.68 (3H ₅ m ₅ CH ₂ ), 3.10-3.25 (3H ₅ m ₅ CH ₂ ), 3.37-3.59 (12H ₅ m, CH ₂ and N-CH) ₅ 3.82 (3H, s ₅ Ar-OCH ₃ ), 3.87(3H ₅ s, Ar-OCH ₃ ), 4.20-4.24 (2H, m, OCH ₂ ), 4.39 (IH ₅ d, CH ₂ ), 5.16 (2H, q, PhCH ₂ ), 6.62 (IH ₅ s, ArH) ₅ 6.77 (IH ₅ s, ArH), 6.83 (IH, s, ArH), 7.26-7.40 (3H, m, PhH), 7.45-7.47 (2H, m, PhH).

Example 36: 2-benzyloχy-3J0-dimemoxy~9~{2-[2-(2-rnethoxy-ethoxy)- ethoxy1-ethoxy>-12-chloro-5,8J3,13a-tetrahvdro-6H-dibenzo [a, g]quinolizine

Compound HA (0.5g, l.lmmol), Cl(CH ₂ CH ₂ O) ₃ CH ₃ (0.66g, 3.6mmol), K ₂ CO ₃ (0.3 Ig, 2.2mmol) and DMF (15ml) was mixed and heat to 100 ⁰ C for 20 hours. After filtering K ₂ CO ₃ , the mixture was concentrated to remove DMF, followed by pouring into water. The aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was

evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ethereum ether) to give yellow powder (0.43g, 65.3%). The analytic sample was recrystallized with ethyl acetate/petroleum ether. ¹ HNMR (CDCl ₃ )δ: 2.44-2.69 (3H, m, CH ₂ ), 3.07-3.23 (3H, m, CH ₂ ), 3.37-3.61 (12H, m ₅ CH ₂ and N-CH), 3.69 (3H, s, OCH ₃ ), 3.82 (3H, s, Ar-OCH ₃ ), 3.87(3H, s, Ar-OCH ₃ ), 4.06~4.14(lH, m, OCH ₂ ) , 4.17-4.23 (IH, m, OCH ₂ ), 4.23-4.31 (IH, d, CH ₂ ), 5.16 (2H, q, PhCH ₂ ), 6.63 (IH, s, ArH) ₅ 6.79 (IH, s, ArH), 6.83 (IH, s, ArH), 7.25-7.41 (3H, m, PhH), 7.45-7.47 (2H, m, PhH).

Example 37 : 2-benzyloxy-3 , 1 O-dimethoxy-9-ethoxyoxaryloxy- 12-chloro- 5,8,13,13 a-tetrahydro - 6/i-dibenzo [a, g] quinolizine

Compound HA (0.2g, 0.44mmol) was dissolved in pyridine (10ml), adding C1COCOOC ₂ H ₅ (0.25ml, 0.66 mmol) under ice bath. The mixture was stirred at room temperature overnight. Then the mixture was concentrated to small volume and added CH ₂ Cl ₂ . After filtering, the filtrate was washed with water, saturated NaHCO ₃ and brine. The solution was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether=l/3) to give desired product (0.1 Ig, 45.2%). ¹ HNMR (CDCl ₃ )δ: 1.32(3H ₅ s, CH ₂ CH ₃ ) 2.46-2.69 (3H, m, CH ₂ ), 3.02-3.20 (3H, m, CH ₂ ), 3.49-3.61 (2H, m, CH ₂ and N-CH), 3.87 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.06~4.14(2H, m, OCH ₂ ), 4.23 (IH, d, CH ₂ ), 5.17 (2H, q, PhCH ₂ ), 6.65(1H, s, ArH), 6.74 (IH, s, ArH), 6.91(1H ₅ s, ArH), 7.29-7.35 (3H, m, PhH), 7.45-7.49 (2H, m, PIiH).

Example 38 : 2,9-diundecanoyloxy-3 , 10-dimethoxy- 12-chloro-5,8, 13,13a- tetrahydro-6i/-dibenzo[a, giquinolizine

A product obtained in Example 1 (0.2g, 0.55mmol) was suspend on CH ₂ Cl ₂ (20ml), adding hendecyl chloride (0.50ml, 1.85mmol) and triethylamine (0.24ml). The mixture was stirred at room temperature for 7 hours. Then the mixture was poured into water, adjusting to pH 9 with saturated NaHCO ₃ . The aqueous phase was extracted with CH ₂ Cl ₂ . The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure.

The residue was purified by silica chromatography to give yellow oil (0.19g, 49.3%0. ¹ HNMR (CDCl ₃ )δ: 0.97 (6H ₅ 2s, 2CH ₃ ), 1.31~1.55(32H, m, CH ₂ ), 2.11~2.23(4H, m, CH ₂ ), 2.61-2.75 (3H, m, CH ₂ ), 3.13~3.16(2H, m, CH ₂ ), 3.28-3.41 (2H ₅ m ₅ CH ₂ ), 3.55-3.57 (IH ₅ m ₅ CH ₂ and N-CH) ₅ 3.80 (3H, S ₅ Ar-OCH ₃ ), 3.81(3H, s, Ar-OCH ₃ ), 3.96(1H ₅ d, CH ₂ ), 6.73(1H, s, ArH), 6.92 (IH, s, ArH), 6.96 (IH, s, ArH).

Example 39: 2-benzyloxy-3J0-dimethoxy-9-undecanoyloxy-12-chloro- 5,8,13,13 a-tetrahydro-6H ^~ -dibenzo [a. g] quinolizine

Compound HA (0.15g, 0.33mmol) was dissolved in pyridine (7ml), adding hendecyl chloride (0.2ml, 0.75mmol). The mixture was stirred at room temperature overnight. Then the mixture was concentrated to remove pyridine and the residue added CH ₂ Cl ₂ . After filtering the insoluble solid, the filtrate was washed with water, saturated NaHCO ₃ and brine. The solution was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give yellow oil (0.16g,78.2%). ¹ HNMR (CDCl ₃ )δ: 0.95 (3H, s, CH ₃ ), 1.32~1.56(16H, m, CH ₂ ), 2.12-2.21(2H, m, CH ₂ ), 2.46-2.68 (3H ₅ m, CH ₂ ), 3.02-3.21 (3H, m, CH ₂ ), 3.49-3.62 (2H, m, CH ₂ and N-CH) ₅ 3.89 (3H ₅ s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.24 (IH, d, CH ₂ ), 5.18 (2H, q, PhCH ₂ ), 6.66(1H, s, ArH), 6.74 (IH, s, ArH), 6.92(1H, s, ArH), 7.29~7.36(3H, m, PhH) ₅ 7.43-7.48 (2H, m, PhH).

Example 40 : 2-benzyloxy-3 , 1 O-dimethoxy-9-f undec- 10-enoyloxy)- 12- chloro-5 , 8 , 13 J 3 a-tetrahydro-6H-dibenzo [a, g] quinolizine

Compound HA (0.15g, 0.33mmol) was dissolved in pyridine (7ml), adding undec-10-enoyl chloride (0.2ml, 0.74mmol). The mixture was stirred at room temperature overnight. Then the mixture was concentrated to remove pyridine and the residue added CH ₂ Cl ₂ . After filtering the insoluble solid, the filtrate was washed with water, saturated NaHCO ₃ and brine. The solution was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give yellow oil (0.15g,73.2%). ¹ HNMR (CDCl ₃ )δ: 1.32~1.56(14H, m, CH ₂ ) , 2.12~2.21(2H, m, CH ₂ ) , 2.46-2.68 (3H, m, CH ₂ ), 3.02-3.21 (3H, m, CH ₂ ), 3.49-3.62 (2H, m, CH ₂ and N-CH), 3.89 (3H ₅ s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.24 (IH ₅ d, CH ₂ ), 4.89-5.10 (2H, m, C=CH ₂ ), 5.18 (2H, q,

PhCH ₂ ), 5.32(1H, m, C=CH) 6.66(1H ₅ s, ArH), 6.74 (IH, s, ArH), 6.92(1H, s, ArH), 7.29~7.36(3H, m, PhH), 7.43-7.48 (2H, m, PhH).

Example 4Jj 2-hvdroxy-3 , 10-dimethoxy-9-undecanoyloxy- 12-chloro-

5,8,13,13 a-tetrahydro-6H-dibenzo [a, g] quinolizine

A product obtained in Example 39 (0.07g, O.llmmol) was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7. The product was given as pale brown oil (0.05g, 85.8 ⁰ Zo) ₁ ¹ HNMR (CDCl ₃ )δ: 0.95 (3H, s, CH ₃ ), 1.32-1.56(16H, m, CH ₂ ), 2.12~2.21(2H, m, CH ₂ )2.58~2.70 (3H, m, CH ₂ ), 3.04-3.24, 3.38-3.39 (3H, m, CH ₂ ), 3.54-3.66 (2H, m, CH ₂ and N-CH), 3.87 (3H, s, Ar-OCH ₃ ), 3.88(3H, s, Ar-OCH ₃ ), 4.25 (IH, d, CH ₂ ), 5.52 (IH, brs, Ar-OH), 6.60 (IH, s, ArH), 6.87 (IH, s, ArH), 6.93 (IH ₃ S ₅ ArH).

Example 42: 2,9-bis-{2-r2-f2-methoxy-ethoxy)-ethoxyl-acetoxyl-3.10- dimethoxy- 12-chloro-5.8,13,13 a-tetrahy dro-6H-dibenzo [a, g] quinolizine

A product obtained in Example 1 (0.22g, O.όlmmol) suspend on CH ₂ Cl ₂ (22ml), adding CH ₃ (OCH ₂ CH ₂ ) ₂ OCH ₂ COC1 (0.25ml, 1.81mmol) and triethylamine (0.24ml). The mixture was stirred at room temperature for 15 hours. Then the mixture was poured into water and extracted with CH ₂ Cl ₂ . The combined organic layers were washed with saturated NaHCO ₃ and brine. The solution was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give yellow oil (0.19g, 45.3%). ¹ HNMR (CDCl ₃ )δ: 2.61-2.75 (3H, m ₅ CH ₂ ), 3.13~3.26(3H, m, CH ₂ ), 3.28-3.41 (6H, m, CH ₃ ), 3.51-3.75 (18H, m, CH ₂ and N-CH), 3.80 (3H, s, Ar-OCH ₃ ), 3.81(3H, s, Ar-OCH ₃ ), 3.96(1H, d, CH ₂ ), 4.16-4.35(4H ₅ m, OCH ₂ ) 6.73(1H, s, ArH), 6.92 (IH, s, ArH), 6.96 (IH, S ₅ ArH).

Example 43j 2-hydroxy-3 , 10-dimethoxy-9- (2- [2-(2-methoxy-ethoxyV ethoxyl -acetoxyl - 12-chloro-5 , 8,13,13 a-tetrahvdro-6H-dibenzo [a, gi quinolizine

Compound IIA (0.2g, 0.44mmol) was dissolved in pyridine (10ml), adding CH ₃ (OCH ₂ CH ₂ ) ₂ OCH ₂ COC1 (0.2ml, 0.72mmol). The mixture was stirred at room temperature overnight. Then the mixture was concentrated to remove pyridine and the

residue was added CH ₂ CI ₂ . After filtering the insoluble solid, the filtrate was washed with water, saturated NaHCO ₃ and brine. The solution was dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography to give 2-hydroxy-3,10-dimethoxy-9-{2-[2-(2-methoxy- ethoxy)-ethoxy] -acetoxy } - 12-chloro-5 , 8,13,13 a-tetrahydro-6H-dibenzo [a, g] quinolizine. The compound is yellow oil (0.23g, 84.2%). ¹ HNMR (CDCl ₃ )δ: 2.61-2.75 (3H, m, CH ₂ ), 3.13~3.26(3H, m, CH ₂ ), 3.28-3.41 (3H, m, CH ₃ ), 3.51-3.75 (1OH, m, CH ₂ and N-CH), 3.80 (3H, s, Ar-OCH ₃ ), 3.81(3H, s, Ar-OCH ₃ ), 3.96(1H, d, CH ₂ ), 4.16~4.35(2H, m, OCH ₂ ), 5.18 (2H, q, PhCH ₂ ), 6.73(1H, s, ArH), 6.92 (IH, s, ArH), 6.96 (IH, S ₅ ArH), 7.29~7.36(3H, m, PhH), 7.43-7.48 (2H, m, PhH).

The product obtained above was hydrogenated in the present of Raney-Ni. The desired product was obtained following the synthetic procedure described in Example 1, 4 or 7.

Example 44 : 2.3.9.10-tetrahvdroxy- 12-chloro-5 ,8.13,13 a-tetrahvdro-6H- dibenzo[a, g] quinolizine

A product obtained in Example 1 (0.3g, 0.66mmol) was dissolved in CH ₂ Cl ₂ (20ml), adding a solution of BBr ₃ (0.32ml) in CH ₂ Cl ₂ (5ml) under ice-salt bath.The mixture was stirred for 1 hours at this temperature, then stirred at room temperature overnight. The reactant solution produced yellow precipitate. The mixture was poured into water and stirred for 30 minitue. After filtering, the solid was dissolved with methanol. Then the mixture was filtered. The filtrate was evaporated under reduced pressure, followed by recrystallizing with methanol to give yellow solid (0.15g, 67.7 %). mp 295-296 ⁰ C. ¹ HNMR (DMSO-d ₆ )δ: 2.65-2.86 (3H, m, CH ₂ ), 3.05~3.63(5H, m, CH ₂ or N-CH) ₅ 4.29 (IH, d, CH ₂ ), 6.59 (IH, s, ArH), 6.81 (IH, s, ArH), 6.92 (IH, s, ArH). MS (EI) m/z: 333(M ⁺ ), 299, 164(base), 107, 80.

Example 45 : 2-hydroxy-3 , 1 O-dimethoxy-9-f 2-hvdroxy-ethoxyV 12-chloro-N- methyl-5.8.13.13 a-tetrahydro-6H-dibenzo | ^" a, g] quinolizine

A product obtained in Example 17 (O.lg) was dissolved in TηF (20ml), adding iodomethane (0.1ml). The mixture was stirred at room temperature overnight. The yellow solid precipitating was filtered and dried to give yellow powder.

Example 46: (-V2-hydroxy-3 , 10-dimethoxy-9-valyloxy- 12-chloro-

5,8,13,13 a-tetrahydro-6H-dibenzo Fa, g] quinolizine

Compound (-)-IIA (preparation as the method reported in CN03151464.2) was treat with N-CBz-L- valine. Accoring the procedure described in method C of Example 26, compound (-)-2-benzyloxy-9-O-(t-Boc-valine)acyl-3,10-dimethoxy- 12-chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a, g]quinolizine was obtaind. This compound was debenzyl with Pd-C/H ₂ (the method described in Example 2). Then the crude product was purified by silica chromatography to give desired product.

Example 47 : f-V2,9-diacetoxy-3 , 10-dimethoxy- 12-chloro-5 ,8 , 13,13a- tetrahydro-6/f-dibenzo [a, g] quinolizine

Compound (-)-IIA was hydrogenated in the present of Raney-Ni according the procedure described in Example 1 to give (— )-2,9-dihydroxy-3,10-dimethoxy-12- chloro-5,8,13,13a-tetrahydro-6H-dibenzo[a, gjquinolizine. This compound was actylation with acetyl anhydride according the method described in Example 6 to give desired product. The total yield is 81%. mp 202-203 ⁰ C. Anal: CachC 61.95%, H 5.43%, N3.14%; test: C 62.18%, H 5.35%, N3.06%. [α] ² _D ⁵ = -254°(C=0.2, CHCl ₃ ). ¹ HNMR (CDCl ₃ )δ: 2.34 (6H, 2s, 2 ^χ COCH ₃ ), 2.58-2.76 (3H, m, CH ₂ ), 3.11~3.17(2H, m, CH ₂ ), 3.28-3.43 (2H ₅ m, CH ₂ ), 3.55 (IH, dd, N-CH), 3.80 (3H, s, Ar-OCH ₃ ), 3.82(3H, s, Ar-OCH ₃ ), 3.99 (IH, d, CH ₂ ), 6.71 (IH, s, ArH), 6.91 (IH, s, ArH), 6.97 (IH, S ₅ ArH). MS(EI) m/z: 445 (M ⁺ ), 444(M-I) ₅ 386(base) ₅ 184, 176, 77.

Example 48 : (-VZ 10-diacetoxy-3 ,9-dimethoxy-5.8.13.13 a-tetrahydro- 6H-dibenzo[a, g] quinolizine

Z-SPD (0.264g, O.δlmmol), pyridine (ImI) and acetyl anhydride (0.5ml) was mixtured and stirred at room temperature for 0.5 hours. The mixture was poured into water, then yellow solid was precipitated. The solid was collected by filtering and wash with water, then dried at 40"C to give pale yellow solid (0.235g, 70.8%). Anal:cacl:C 67.14%, H 6.12%, N 3.40%; test: C 67.46%, H 5.97%, N3.30%. ¹ HNMR (CDCl ₃ )δ:2.32 (6H ₅ 2s, 2*COCH ₃ ), 2.61-2.91 (3H, m, CH ₂ ), 3.14-3.29 (3H, m, CH ₂ ), 3.51-3.60 (2H, m ₅ CH ₂ and N-CH), 3.81 (3H ₅ s, Ar-OCH ₃ ), 3.82(3H ₅ s, Ar-OCH ₃ ), 4.20 (IH, d, J=15.9Hz, CH ₂ ), 6.71 (IH, s, ArH) ₅ 6.90 (2H ₅ s, ArH) ₅ 6.92 (IH, S ₅

ArH)MS(EI) m/z:411 (M ⁺ ), 368, 220, 176, 150(base), 135.

Example 49j ( ^" -)-2-benzyloxy-3 , 10-dimethoxy-9-acetoxy- 12-chloro-

5,8,13,13 a-tetrahvdro-6H-dibenzo fa, g] quinolizine

Starting from compound (~)-IIA, the desired product was obtained following the synthetic procedure described in Example 6 to give white powder. It can be used in next step without purification.

Example 5C); (-)-2-hydroxy-3 , 10-dimethoxy-9-acetoxy- 12-chloro-

5,8,13,13 a-tetrahy dro -6H-dibenzo [a, g] quinolizine

Starting from the product obtained in Example 49, the desired product was obtained following the synthetic procedure described in Example 7 to give pink powder. The total yield from compound HA was 63.26%. mp 172~173 ⁰ C. Anal: calcd: C 62.45%, H 5.49%, N 3.47%; test: C 62.31%, H 5.33%, N 3.28%. [α] ² _D ⁵ = -235°(CHC1 ₃ ). MS(EI) m/z:405 (M+2), 403 (M ⁺ ), 360, 344(base), 186, 149, 91.

Example 51 : (-)-2,9-bis-(N-benyloxycarbonyl-varyloxy)-3 , 10-dimethoxy- 12-chloro-5 ,8 , 13,13 a-tetrahydro-6H-dibenzo [a, g] quinolizine

Compound (-)-IIA was hydrogenated in the present of Raney-Ni according the procedure described in Example 1 to give (-)-2,9-dihydroxy-3,10-dimethoxy-12- chIoro-5, 8,13, 13a- tetrahydro-6i/-dibenzo[a, g]quinolizine.

The methanesulfonate of this compound (0.6g, 1.3mmol), N-CBz- valine (1.32g, 5.26mmol), DCC (1.08g, 5.24mmol) and DMAP (0.16g, 1.31mmol) was mixed with CH ₂ Cl ₂ (20ml) and stirred at room temperature for 6 hours. Then the mixture was cooled in refrigeratory. Afer filtered, the filtrate was evaporated under reduced pressure. The crude product was purified by silica chromatography (ethyl acetate/petroleum ether) to give pale yellow solid (l.Olg, 93.1%). The analytic sample was recrystallized with ethyl acetate/petroleum ether. ¹ HNMR (CDCl ₃ )δ:1.04 (6H, d, 2 ^χ CH ₃ ), 1.11 (6H, d, 2xCH ₃ ), 2.40-2.47 (2H, m, CH ₂ ), 2.60-2.74 (3H, m, CH ₂ ), 3.09-3.15 (2H, m, CH ₂ and CH), 3.29-3.57 (3H, m, CH ₂ and N-CH), 3.76 (3H, s, Ar-OCH ₃ ), 3.78(3H, s, Ar-OCH ₃ ), 3.98 (IH, d, J=12Hz, CH ₂ ), 4.62 (2H, m, COCH), 5.16 (4H, s, OCH ₂ Ph), 5.34 (IH, d, NH), 5.39 (IH, d, NH), 6.69 (IH, s, ArH), 6.89 (IH, s, ArH), 6.95 (IH, d, ArH), 7.32-7.40 (1OH, m, PhH).

Example 52 : C-V2-benzyloxy-3 , 1 O-dimethoxy-9-ethoxycarbonylrnethoxy- 12-chloro-5,8, 13,13 a-tetrahydro-6i7-dibenzora, giquinolizine

Compound (-)-IIA (1.Og, 2.2mmol) was dissolved in dry DMF (10ml), adding BrCH ₂ COOC ₂ H ₅ (0.27ml, 2.4mmol), K ₂ CO ₃ (0.6 Ig, 4.4mmol). The mixture was stirred at room temperature for 6 hours. After filtering K ₂ CO ₃ , the filtrate was concentrated to remove DMF, followed by adding water. The aqueous phase was extracted two times with CH ₂ Cl ₂ . The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved with ethyl acetate and filtered. The filtrate was recrystallized with ethyl acetate/petroleum ether to give white powder (0.4g, 34%).

Example 53: 2-benzyloxy-3 , 1 O-dimethoxy-9-ethoxycarbonylmethoxy-

12-chloro- 5,8J3,13a-tetrahydro-6H-dibenzo[a, glquinolizine

The desired product was obtained following the synthetic procedure described in Example 52. The crude product was purified by silica chromatography to give milk white powder, mp 134 ⁰ C. ¹ HNMR (CDCl ₃ )δ:1.31 (3H, t, CH ₃ ), 2.46-2.70 (3H, m, CH ₂ ), 3.10-3.21 (3H, m, CH ₂ ), 3.46 (IH, dd, N-CH ₂ ), 3.53 (IH, d, CH ₂ ), 3.81 (IH, s, Ar-OCH ₃ ), 3.88 (IH, s, Ar-OCH ₃ ), 4.26 (2H, q, OCH ₂ CH ₃ ), 4.35 (IH, d, CH ₂ ), 4.63 (2H, q, OCH ₂ CO), 5.16 (2H, q, PhCH ₂ O), 6.64 (IH, s, ArH), 6.78 (IH, s, ArH), 6.84 (IH, S ₃ ArH), 7.27-7.40 (3H, m, PhH), 7.45-7.48 (2H ₃ m, PhH).

Example 54: (— )-2-hydroxy-3,10-dimethoxy-9-ethoxycarbonylmethoxy- 12-chloro-5 ,8,13,13 a-tetrahydro-6if-dibenzo Fa, g] quinolizine

Starting from the product obtained in Example 52, the desired product was obtained following the synthetic procedure described in Example 1 to give pale yellow powder. The analytic sample was recrystallized with ethyl acetate/petroleum ether, mp 202-204 ⁰ C. ¹ HNMR (CD ₃ OD)δ:1.26 (3H, t, CH ₃ ), 2.84-3.11 (2H, m, CH ₂ ), 3.22-3.34 (4H, m, CH ₂ ), 3.55 (IH, td, N-CH), 3.71-3.82 (IH, d, CH ₂ ), 3.86 (IH ₃ s, Ar-OCH ₃ ), 3.88 (IH, s, Ar-OCH ₃ ), 4.20 (2H, q, OCH ₂ CH ₃ ), 4.50 (IH, d, CH ₂ ), 4.76 (2H, q, OCH ₂ CO) ₃ 5.07 (2H, q, PhCH ₂ ), 6.83 (IH, s, ArH) ₃ 6.85 (IH, s, ArH), 7.21 (IH, S ₅ ArH).

Example 55: 2-hydroxy-3,10-dimethoxy-9-ethoxycarbonylmethoxy-12-

chloro-5 ,8 , 13 J 3a-tetrahydro-6H-dibenzo Fa, g] quinolizine

Starting from the product obtained in Example 53, the desired product was obtained following the synthetic procedure described in Example 54 to give milk white powder, mp 132 ⁰ C.

Example 56; (->2-hydroxy-3 , 10-dimethoxy-9-carboxymethoxy- 12- chloro-5, 8, 13,13a- tetrahydro-ό/i-dibenzofa, g] quinolizine

A product obtained in Example 54 (1.92g, 4.3mmol) was dissolved in ethanol (20ml), adding NaOH (0.343g, 8.6mmol, dissolved in. 10ml water). The mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated under reduced pressure followed by adding water. The aqueous phase was washed with ethyl acetate and adjust to pH 3-4 by lmol/L hydrochloric acid. The precipitated solid was collected by filtration and washed by water. Recrystallizing with methanol/water to give yellow powder (UIg, 62%). mp 179-180 ⁰ C. [α] ² _D ⁵ = -149°(CH ₃ OH). ¹ HNMR (DMSO-d ₆ )δ:2.40~2.50 (2H, m, CH ₂ ), 2.65-2.76 (2H, m, CH ₂ ), 2.91-2.99 (IH, m, CH ₂ ), 3.30-3.56 (3H, m, CH ₂ and N-CH), 3.74 (IH, s, Ar-OCH ₃ ), 3.80 (IH, s, Ar-OCH ₃ ), 4.41 (IH, d, CH ₂ ), 4.63 (2H, q, OCH ₂ CO), 6.69 (IH, s, ArH), 6.76 (IH, s, ArH), 7.12 (1H, S ₅ ArH).

Example 57: 2-hvdroxy-3,10-dimethoxy-9-carboxymethoxy-12-chloro- 5,8,13,13a-tetrahydro- 6/j-dibenzo[ ^" a, g] quinolizine

A product obtained in Example 55 (3.1g, 6.9mmol) was dissolved in ethanol (50ml), adding lmol/L NaOH (13.9ml). The mixture was stirred at room temperature for 2 hours. Then the mixture was concentrated under reduced pressure followed by adding water. The aqueous phase was washed with ethyl acetate and adjust to pH 5-6 by lmol/L hydrochloric acid. The precipitated solid was collected by filtration and washed by water to give pale yellow powder. The solid was dissolved in alkli solution and adjust the pH again to give the refine product (2.6g, 89.5%). mp 172-174 ⁰ C. ¹ HNMR (DMSO-d ₆ )δ: 2.30-2.49 (2H, m, CH ₂ ), 2.58-2.63 (IH, d, CH ₂ ), 2.89-2.95 (IH, m, CH ₂ ), 3.08 (IH, dd, CH ₂ ), 3.23 (IH, dd, N-CH), 3.38-3.47 (2H, m, CH ₂ ), 3.74 (3H, s, Ar-OCH ₃ ), 3.79 (IH, s, Ar-OCH ₃ ), 4.25 (IH, d, CH ₂ ), 4.59 (2H, q, OCH ₂ CO), 6.66 (IH, s, ArH), 6.73 (IH, s, ArH), 7.05 (IH, s, ArH).

Example 58 : 2-benzyloxy-3.10-dimethoxy-9-carboxymethoxy- 12-chloro- 5.8.13,13 a-tetrahvdro- 6H-dibenzo fa, g] quinolizine

Starting from the product obtained in Example 53 (0.32g, 0.59mmol), the desired product was obtained following the synthetic procedure described in Example 57 to give pale yellow powder (0.22g, 73.7%). ¹ HNMR (DMSO-d ₆ )δ: 2.30 (IH, dd, CH ₂ ), 2.58-2.69 (2H, m, CH ₂ ), 2.89-2.95 (IH, m, CH ₂ ), 3.14 (IH, d, CH ₂ ), 3.32 (IH, dd, N-CH), 3.39-3.49 (2H, m, CH ₂ ), 3.74 (3H, s, Ar-OCH ₃ ), 3.79 (IH, s, Ar-OCH ₃ ), 4.30 (IH, d, CH ₂ ), 4.61 (2H, q, OCH ₂ CO), 5.07 (2H, s, OCH ₂ Ph), 6.73 (IH, s, ArH), 6.98 (IH, s, ArH), 7.07 (IH, s, ArH), 7.29-7.48 (5H, s, PhH).

Starting from the product descried above (Example 58), the product in Example 57 was also obtained following the synthetic procedure described in Example 55.

Example 59 : (-)-2,9-diethoxycarbonylmethoxy-3 , 10-dimethoxy- 12-chloro- 5,8, 13 , 13a-tetrahydro-6/f-dibenzo| ^~ a, gjqumolizine

Compound (-)-IIA was hydrogenated in the present of Raney-Ni according to the procedure described in Example 1 to give (-)-2,9-dihydroxy-3,l O-dimethoxy- 12- chloro-5,8,13,13a- tetrahydro-6H-dibenzo[a, g]quinolizine.

The compound described above (3.3g, 9.1mmol) was dissolved in dry DMF (10ml), adding BrCH ₂ COOC ₂ H ₅ (2.53ml) and K ₂ CO ₃ (3.78g). The mixture was stirred at room temperature for 2 hours. After filtering K ₂ CO ₃ , the filtrate was concentrated to remove DMF, followed by diluting with water. The aqueous phase was extracted two times with CH ₂ Cl ₂ . The combined organic layers were washed with brine and dried over Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica chromatography (ethyl acetate/petroleum ether) to give compounds 59a N 59b and 59c.

59a:(->2.9-diethoxycarbonylmethoxy-3.10-dimethoxy- 12-chloro-5,8, 13,13a- tetrahydro-6H-dibenzo[a, glquinolizine

Crude compound 59a was recrystallized with ethyl acetate/petroleum ether to give desired white powder (1.3g, 26.7%). ¹ HNMR (CD ₃ Cl)δ: 1.31 (6H, t, CH ₃ x2), 2.55-2.71 (3H, m, CH ₂ ), 3.08-3.32 (3H, m, CH ₂ ), 3.48-3.57 (2H, m, CH ₂ and N-CH), 3.81 (3H ₃ s, Ar-OCH ₃ ), 3.87 (3H, s, Ar-OCH ₃ ), 4.22-4.33 (4H, m, OCH ₂ CH ₃ ^), 4.37

(IH, d, CH ₂ ), 4.55-4.75 (4H ₃ q, OCH ₂ COx2), 6.64 (IH, s, ArH), 6.79 (IH, s, ArH) ₅ 6.84 (1H ₅ S ₅ ArH).

59b:(-V2,9-diethoxycarbonylmethoxy-3.10-dimethoxy-12-chlo ro-N-α- ethoxγcarbonylmethyl-5 ,8,13,13 a-tetrahydro-6//-dibenzo [a, g] quinolizine

Compound 59b (0.15g, 2.3%) was yellow powder. ¹ HNMR (CD ₃ Cl)δ: 1.28 (9H ₅ m, CH ₃ x3), 2.84 (IH ₅ m, CH ₂ ), 3.17-3.25 (2H ₅ m ₅ CH ₂ ), 3.42-3.64 (2H ₅ m ₅ CH ₂ ), 3.84 (3H ₅ s, Ar-OCH ₃ ), 3.89 (3H ₅ s, Ar-OCH ₃ ), 4.16-4.31 (6H ₅ m ₅ OCH ₁ CH ₃ XS) ₅ 4.59 (IH, m, CH ₂ ), 4.65 (2H ₅ m ₅ OCH ₂ CO), 4.71 (2H ₅ s, NCH ₂ CO), 4.95 (IH, d, CH ₂ or N-CH), 5.44 (IH, d, CH ₂ ), 5.68 (2H, q, OCH ₂ CO) ₅ 6.13 (IH, m, CH ₂ ), 6.74 (IH, s, ArH) ₅ 6.82 (IH ₅ S ₅ ArH), 6.95 (IH, S ₅ ArH).

59c:(-)-2,9-diethoxycarbonylmethoxy-3 , 10-dimethoxy- 12-chloro-N-β- ethoxycarbonylmethyl-5,8,13,13a-tetrahvdro-6H-dibenzo| ^" a, glquinolizine

Compound 59c (0.2g ₅ 3.1%) was yellow powder. ¹ HNMR (CD ₃ Cl)δ: 1.28 (9H, m, CH ₃ x3), 2.68-2.78 (IH, m, CH ₂ ), 3.01 (IH, m, CH ₂ ), 3.26 (IH, m, CH ₂ ), 3.72 (2H, m, CH ₂ ), 3.85 (3H ₅ s, Ar-OCH ₃ ), 3.89 (3H ₅ s, Ar-OCH ₃ ), 4.11-4.33 (6H, m, OCH ₂ CH ₃ XS), 4.62 (2H, m, OCH ₂ CO) ₅ 4.72 (IH, m, CH ₂ ), 4.81 (2H, s, NCH ₂ CO), 4.98 (IH ₅ d, OCH ₂ CO) ₅ 5.22 (IH, d, CH ₂ or N-CH), 5.64 (IH, d, OCH ₂ CO), 5.93 (IH ₅ d, CH ₂ ), 6.49 (IH, m, CH ₂ ), 6.73 (IH ₅ s, ArH) ₅ 6.83 (IH ₅ s, ArH), 7.00 (IH, s, ArH).

Example 60: 2,9-diethoxycarbonylmethoxy-3,10-dimethoxy-12-chloro- 5,8,13,13 a-tetrahydro-6H-dibenzo [a, g] quinolizine

The desired product was obtained following the synthetic procedure described in Example 59.

Example 6Jj f-)-2,9-dicarboxymethoxy-3 , 10-dimethoxy- 12-chloro-

5,8.13,13a-tetrahydro-6i/- dibenzofa, g]quinolizine

Starting from the product obtained in Example 59a (1.33g, 2.49mmol), the desired product was obtained following the synthetic procedure described in Example 56 to give yellow powder (0.653g, 54.9%). mp 230-232 ⁰ C. ¹ HNMR (DMSO-d ₆ )δ: 2.24-2.33 (IH, m ₅ CH ₂ ), 2.60-2.64 (IH ₅ d, CH ₂ ), 2.86-2.95 (IH ₅ m, CH ₂ ), 3.05 (IH ₅ dd, CH ₂ ), 3.26 (IH ₅ dd ₅ N-CH), 3.36-3.42 (3H ₅ m, CH ₂ ), 3.74 (3H ₅ s, Ar-OCH ₃ ), 3.76 (IH ₅ s ₅ Ar-OCH ₃ ), 4.25 (IH ₅ d ₅ CH ₂ ), 4.51 (4H ₅ S ₅ OCH ₂ CO) ₅ 6.71 (IH, s, ArH), 6.81

(IH, s, ArH), 7.01 (IH, s, ArH). MS(EI) m/z: 478 (M ⁺ ), 476 (M-2), 418(base), 344, 183, 91, 77.

Example 62 : 2.9-dicarboxymethoxy-3 , 10-dimethoxy- 12-chloro-5 ,8, 13,13a- tetrahydro- 6/f-dibenzo | ^" a, elguinolizine

Staring from the product obtained in Example 60, the desired product was obtained following the synthetic procedure described in Example 61 to give yellow powder. Yield:90%. mp 202-204 ⁰ C. ¹ HNMR (DMSO-d ₆ )δ: 2.25-2.34 (IH, m, CH ₂ ), 2.60-2.65 (IH, d, CH ₂ ), 2.86-2.90 (IH, m, CH ₂ ), 3.05 (IH, dd, CH ₂ ), 3.27 (IH, dd, N-CH), 3.37-3.44 (3H, m, CH ₂ ), 3.77 (3H, s, Ar-OCH ₃ ), 3.78 (IH, s, Ar-OCH ₃ ), 4.25 (IH, d, CH ₂ ), 4.52 (4H, s, OCH ₂ CO), 6.71 (IH, s, ArH), 6.81 (IH, s, ArH), 7.02 (IH, s, ArH).

Example 63 : 2,3-methylenedioxyl-9, 10-dimethoxy-12-fluoro-5,8, 13 , 13a- tetrahydro-6H-dibenzo [a, g] quinolizine

2,3-metliylenedioxyl-9,10-dimethoxy-12-amino-5,8,13,13a-tetr ahydro-6H-diben zo[a, g]quinolizine (0.1 g, 0.28 mmol) was suspend on HBF ₄ (5 mL), cooling to -10 ^° C in ice-salt bath. A solution Of NaNO ₂ (0.19 g) in water (1.5 mL) was dropped slowly to control the temperature <-8 ⁰ C. When finished, the mixture was stirred in ice bath for 0.5-1 hours, followed cooling in refrigeratory. The precipitate was collected by filtering and washed by cool water and cool ethanol to give pale yellow powder (0.12 g). The powder was pyrolyzed in 110 ⁰ C. The crude product was purified by silica chromatography (CH ₂ Cl ₂ /methanol) to give pale yellow powder (0.05 g, 49.6%). ¹ H NMR (CDCl ₃ ) δ: 2.57-2.69 (3H, m, CH ₂ ), 3.13-3.22 (2H, m, CH ₂ ), 3.31 ( IH, dd, CH ₂ ), 3.34-3.55 (2H, m, CH ₂ and N-CH), 3.80 (3H, s, Ar-OCH ₃ ), 3.83 (3H, s, Ar-OCH ₃ ), 4.23 (IH, d, CH ₂ ), 5.92 (2H, s, OCH ₂ O), 6.56 (IH, s, Ar-H), 6.59 (IH, s, Ar-H), 6.76 (IH, s, Ar-H). MS(EI) m/z: 357 (M ⁺ ), 326, 182, 167(base), 149. MS (HR-EI) m/z: 357.1380 (M ⁺ ); calcd: 357.1376.