WO2016021192A1 - Process for production of (s)-(tetrahydrofuran-3-yl)hydrazine - Google Patents

Abstract

A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof, comprising hydrolysis or hydrogenation step of protected hydrazine compound of formula VII, wherein R^a is a tert-butyl group or a benzyl group, is disclosed. (S)-(Tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof is a useful intermediate in the preparation of a PDE9 inhibitor.

Description

PROCESS FOR PRODUCTION OF (S)-(TETRAHYDROFURAN-3-YL)HYDRAZINE

The present disclosure relates to a process for production of chiral hydrazine derivatives or acid addition salts thereof, which are useful intermediates in the preparation of PDE9 inhibitors for NO-cGMP signaling enhancement compounds. More preferably, the present disclosure also relates to a new compound used in the production process.

1H-Pyrazolo[4,3-c]quinolin-4(5H)-one derivatives are being developed in the key therapeutic area especially for treatment of Cognitive disorders. In the synthesis of these compounds, (S)-(tetrahydrofuran-3-yl)hydrazine or an acid addition salt thereof is used for building of fused pyrazole ring (PTL 1).

PTL 1 discloses (S)-(tetrahydrofuran-3-yl)hydrazine of formula I below and its derivatives as useful intermediates in the synthesis of 1H-pyrazolo[4,3-c]quinolin-4(5H)-one derivatives.

PTL 1 also discloses the production process of the compound of Formula I as follows;

The above chemistry involves use of toxic reagents like methyl hydrazine, 1,4-dioxane and diethyl azodicarboxylate (DEAD).

Methods and materials involved in above publications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible. The long synthesis and fewer yields obtained than industrial standard does not make the process economically viable on commercial scale.

A various processes are disclosed for synthesis of alkyl hydrazine compounds starting from respective ketone derivatives.

The process depicted in below synthetic scheme is disclosed in NPL 1,

The process for the preparation of chiral hydrazine disclosed in Haddad et al. involves the use of chiral catalysts and ligands for reduction of ketone derived hydrazone compounds. The commercial availability and the cost of these catalysts and ligands limit the use of this chemistry on commercial scale. Further the optical purity (% ee) obtained by the above procedure is 72% and requires additional chiral resolution to enhance the optical purity which reduces the overall yield, in turn increases the cost.

[PTL 1] US patent 8,563,565

[NPL 1] Haddad et al., "Catalytic asymmetric hydrogenation of heterocyclic ketone-derived hydrazones, pronounced solvent effect on the inversion of configuration", Tetrahedron Let., 52 (2011), 29, 3718–3722

A need remains for an improved and commercially viable chemistry for preparation of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof with low cost, high yields and high purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation. Desirable process properties include non-hazardous conditions, environmentally friendly and easy to handle reagents, reduced reaction times, reduced cost, greater simplicity, increased purity, no by-product formation which is difficult to separate, and increased yield of the product, thereby enabling the production of 1H-pyrazolo[4,3-c]quinolin-4(5H)-one derivatives, and their pharmaceutically acceptable acid addition salts in high purity, high yield and low cost.

In such circumstances, the present inventors have conducted intensive studies and have found the present invention.

The present invention relates to the following.
<1> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof, comprising (e) hydrolysis or hydrogenation step of protected hydrazine compound of formula VII,

wherein R^a is a tert-butyl group or a benzyl group.
<2> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <1>, comprising (d) reacting step of the compound of formula V with the compound of formula VI to produce the protected hydrazine compound of formula VII, and (e) hydrolysis or hydrogenation step of the protected hydrazine compound of formula VII,

wherein R^a is the same definition as in <1>, OE is an ester residue of sulfonic acid, phosphonic acid and phosphoric acid selected from the group consisting of

wherein R^b is i) a C1-6 alkyl group optionally substituted with one to five halogen atoms, or ii) a C6-14 aryl group optionally substituted with one to three substituents selected from the group consisting of a C1-6 alkyl group, a halogen atom and a nitro group.
<3> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <2>, comprising (c) reacting step of the compound of formula IV with an esterifying reagent to produce the compound of formula V, (d) reacting step of the compound of formula V with the compound of formula VI to produce the protected hydrazine compound of formula VII, and (e) hydrolysis or hydrogenation step of the protected hydrazine compound of formula VII,

wherein R^a and OE are the same definitions as in <2>.
<4> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <3>, comprising (b) reacting step of the compound of formula III in acidic or basic conditions to produce the compound of formula IV, (c) reacting step of the compound of formula IV with an esterifying reagent to produce the compound of formula V, (d) reacting step of the compound of formula V with the compound of formula VI to produce the protected hydrazine compound of formula VII, and (e) hydrolysis or hydrogenation step of the protected hydrazine compound of formula VII,

wherein R^a and OE are the same definitions as in <3>, and X is a halogen atom.
<5> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <4>, comprising (a) reduction step of the compound of formula II to produce the compound of formula III, (b) reacting step of the compound of formula III in acidic or basic conditions to produce the compound of formula IV, (c) reacting step of the compound of formula IV with an esterifying reagent to produce the compound of formula V, (d) reacting step of the compound of formula V with the compound of formula VI to produce the protected hydrazine compound of formula VII, and (e) hydrolysis or hydrogenation step of the protected hydrazine compound of formula VII,

wherein R^a, OE and X are the same definitions as in <4>, R^c is a C1-6 alkyl group, a C6-14 aryl group or a C3-8 cycloalkyl group.
<6> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <1>, wherein R^a is a tert-butyl group.
<7> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <2>, wherein R^a is a tert-butyl group, and OE is a 4-methylbenzenesulfonyloxy group.
<8> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <3>, wherein R^a is a tert-butyl group, and OE is a 4-methylbenzenesulfonyloxy group.
<9> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <4>, wherein R^a is a tert-butyl group, OE is a 4-methylbenzenesulfonyloxy group, and X is a chlorine atom.
<10> A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as described in <5>, wherein R^a is a tert-butyl group, OE is a 4-methylbenzenesulfonyloxy group, X is a chlorine atom, and R^c is an ethyl group.
<11> A compound of formula VII

wherein R^a is a tert-butyl group or a benzyl group.
<12> A compound of formula VII as described in <11>, wherein R^a is a tert-butyl group.

In one aspect, the present disclosure relates to a large scale and economical chemistry for the preparation of chiral hydrazine derivatives or its acid addition salts, which are useful intermediates in the preparation PDE9 inhibitor for NO-cGMP signaling enhancement compounds.

In another aspect, the present disclosure also relates to an intermediate compound of formula VII or VIII which is novel and useful for the preparation of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof.

Still in another aspect, the present disclosure particularly relates to a novel, commercially viable and industrially advantageous chemistry for the preparation of a substantially pure (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof. The compound of formula I is useful for preparing various pharmaceutically active compounds or a pharmaceutically acceptable salt thereof, in high yield and high purity.

The new chemistry avoids the tedious and cumbersome procedures of the prior processes and is convenient to operate on a commercial scale.

Still further in another aspect, the present disclosure also encompasses the use of pure (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof obtained by the process disclosed herein for preparing 1H-pyrazolo[4,3-c]quinolin-4(5H)-one derivatives or pharmaceutically acceptable salts thereof.

The process for the preparation of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof disclosed herein has the following advantages over the processes described in the prior art:
i) the overall chemistry involves a reduced number of process steps and shorter reaction times;
ii) the process avoids the use of hazardous or toxic chemicals like sodium cyanoborohydride, methylhydrazine, 1,4-dioxane, diethyl ether etc.;
iii) the process avoids the use of tedious and cumbersome procedures like column chromatographic purifications and chiral separations;
iv) the process involves easy work-up methods and simple isolation processes, and there is a reduction in chemical waste;
v) the purity of the product is increased without additional purifications; and
vi) the overall yield of the product is increased.

Meaning of symbols, terms and the like are as follows.

The term “halogen atom” represents a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like, and preferably a fluorine atom, a chlorine atom or a bromine atom.

The term “C1-6 alkyl group” represents a linear or branched alkyl group having 1 to 6 carbon atoms. Preferable examples of the groups include, for example, a methyl group, an ethyl group, a n-propyl group, an i-propyl group, a n-butyl group, an i-butyl group, a tert-butyl group, a n-pentyl group, an i-pentyl group, a neopentyl group, an n-hexyl group, a 1-methylpropyl group, a 1,1-dimetylbutyl group, a 2,2-dimetylbutyl group, a 2-ethylbutyl group, a 1,3-dimethylbutyl group, a 2-methylpentyl group, and the like.

The term “C6-14 aryl group” represents an aromatic hydrocarbon ring group having 6 to 14 carbon atoms. Preferable examples of the group include a phenyl group, a tolyl group, a 1-naphtyl group, a 2-naphtyl group, an indenyl group, an azulenyl group, a heptalenyl group, an indacenyl group, a biphenylyl group, an acenaphthylenyl group, a fluorenyl group, a phenalenyl group, a phenanthrenyl group, an anthracenyl group, and the like.

The term “C3-8 cycloalkyl group” represents a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms. Preferable examples of the group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and cyclooctyl group.

According to one aspect, there is provided a chemistry for preparing (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as the following scheme:

wherein R^c is a C1-6 alkyl group, a C6-14 aryl group or a C3-8 cycloalkyl group, preferably ethyl group; X is a halogen atom, preferably a chlorine atom; OE is the ester residue group selected from the group consisting of

wherein R^b is a C1-6 alkyl group optionally substituted by one to five halogen atoms or a C6-14 aryl group optionally substituted by one to three substituents selected from the group consisting of a C1-6 alkyl group, a halogen atom and a nitro group, preferably methanesulfonyloxy group, benzensulfonyloxy group or 4-methylbenzenesulfonyloxy group; R^a is a tert-butyl group or a benzyl group, preferably a tert-butyl group.

The process for producing (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salts thereof includes 5 steps as follows.

1. The first step is reduction of the compound of formula II to produce the compound of formula III.

The reducing agent includes, for example, but not limited to, borane-methyl sulfide complex, borane-tetrahydrofuran complex, diborane, lithium aluminum hydride, a metal salt of boron hydride or a mixture of a metal salt of boron hydride and methanol. A mixture of an alkali metal salt of boron hydride and methanol or a mixture of an alkaline earth metal salt of boron hydride and methanol is more preferred. A mixture of sodium borohydride and methanol is further more preferred. A mixture of metal salt of boron hydride and methanol forms a metal salt of methoxyborohydride in the reaction solution, in situ.

The metal salt of boron hydride is used in 0.5 to 2.0 equivalents, preferably in 0.8 to 1.2 equivalents, based on the compound of formula II. Methanol is used in 0.5 to 2.0 equivalents, preferably in 0.8 to 1.5 equivalents, based on the metal salt of boron hydride.

The solvent may be ethanol, isopropyl alcohol, n-propanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dimethoxymethane, diethoxyethane, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloromethane, chloroform and a mixture thereof; and preferably toluene, 2-methyltetrahydrofuran, ethanol, isopropyl alcohol, tetrahydrofuran and a mixture thereof.

The reaction is carried out at a temperature of about -20°C to about 60°C, preferably at a temperature of about -10°C to about 40°C, and more preferably at a temperature of about 20°C to about 30°C. The reaction time may vary between about 10 hours to about 40 hours, preferably about 10 hours to about 30 hours, and more preferably about 15 hours to about 20 hours.

The reaction mass containing the compound of formula III may be subjected to usual work up such as a washing, an extraction, a pH adjustment, evaporation, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula IV, or the compound of formula III may be isolated and then used in the next step.

The compound of formula III is isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.

The solvent used to isolate the compound of formula III may be water, an aliphatic ether, a hydrocarbon solvent, a chlorinated hydrocarbon and a mixture thereof. Preferably, the solvent may be water, dichloromethane, n-heptane, n-pentane, n-hexane, cyclohexane, methyl tert-butyl ether and a mixture thereof. A most preferable solvent is methyl tert-butyl ether.

In the case that the reaction mass is used directly in the next step to produce the compound of formula IV, the reaction mass containing the compound of formula III obtained is concentrated and then taken for the next step.

2. The second step is a reaction of the compound of formula III in the presence of an acid or a base to produce the compound of formula IV.

The acid used in this step includes, for example, but are not limited to, an inorganic acid or an organic acid. Preferably, the acid may be hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, p-toluene sulfonic acid, trifluoroacetic acid and a mixture thereof.

The base used in this step is an organic base or an inorganic base. Preferably the organic base is triethylamine, trimethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine or 1,8-diazabicycloundec-7-ene. Preferably the inorganic base is sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide or potassium tert-butoxide, and more preferably sodium bicarbonate, sodium carbonate and potassium carbonate.

This reaction step may be performed with or without a solvent. The reaction medium has a boiling point of at least about 75°C. Preferably, the reaction medium has a boiling point of at least about 90°C. Most preferably, the reaction medium has a boiling point in the range from about 95°C to about 120°C.

Preferable solvent is water, toluene, xylene, a C2-4 alcohol (e.g., ethanol, propanol, isopropanol, 1-butanol, 2-butanol and tert-butanol), 1,2-dichloroethane, ethyl acetate or a mixture thereof. More preferable solvent is toluene, xylene, a C3-4 alcohol, water or a mixture thereof.

The reaction is carried out at a temperature of about 80°C to about 200°C, preferably at a temperature of about 90°C to about 150°C, and more preferably at a temperature of about 95°C to about 110°C. The reaction time may vary between about 1 hour to about 10 hours, preferably about 2 hours to about 7 hours, and more preferably about 3 hours to about 5 hours.

The reaction mass containing the compound of formula IV may be subjected to usual work up such as a washing, an extraction, a pH adjustment, evaporation, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula V, or the compound of formula IV may be isolated and then used in the next step.

The compound of formula IV is isolated from a suitable solvent by conventional methods such as cooling, partial removal of the solvent from the solution, evaporation, vacuum distillation, or a combination thereof.

The reaction mass containing the compound of formula IV obtained is isolated as a liquid in crude or pure form and then taken for the next step.

3. The third step is a reaction of the compound of formula IV with an esterifying agent in the presence of a base to produce the compound of formula V.

The esterifying agent is, for example, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, diethyl chlorophosphonate; and preferably methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride.

The solvent may be tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, cyclopentyl methyl ether, dimethoxyethane, diethoxyethane, n-pentane, n-hexane, n-heptane, cyclohexane, ethyl acetate, isopropyl acetate, n-propyl acetate, butyl acetate, tert-butyl acetate, toluene, xylene, dichloromethane, dichloroethane, chloroform and a mixture thereof; and preferably toluene, cyclopentyl methyl ether, 2-methyltetrahydrofuran, tetrahydrofuran and a mixture thereof.

The base used in this step is an organic base or inorganic base. Preferably the organic base is, for example, triethylamine, trimethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine, 1-methylimidazole, 1,8-Diazabicycloundec-7-ene or a mixture thereof, and more preferably triethylamine, N,N-diisopropylethylamine , N-methylmorpholine, 1-methylimidazole and a mixture thereof. Preferably the inorganic base is, for example, but not limited to, sodium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate or a mixture thereof.

The reaction temperature is about -20°C to about 50°C, preferably at a temperature of about -10°C to about 40°C, and more preferably at a temperature of about 10°C to about 30°C. The reaction time may vary from about 1 hour to about 8 hours, preferably about 2 hours to about 5 hours, and more preferably about 2 hours to about 3 hours.

The reaction mass containing the compound of formula V obtained in this step may be subjected to usual work up such as a washing, an extraction, a pH adjustment, evaporation, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula VII, or the compound of formula V may be isolated and then used in the next step.

The compound of formula V is isolated from a suitable solvent by conventional methods such as cooling, partial removal of the solvent from the solution, evaporation, vacuum distillation, or a combination thereof.

The reaction mass containing the compound of formula V obtained is isolated as liquid in crude or pure form and then taken for the next step.

4. The fourth step is the reaction of the compound of formula V with the compound of formula VI in the presence of base to produce the compound of formula VII.

The base used in this step is an organic base or inorganic base. Preferably the organic base is triethylamine, trimethylamine, N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine or 1,8-Diazabicycloundec-7-ene. Preferably the inorganic base is sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium tert-butoxide, sodium isopropoxide or potassium tert-butoxide, and more preferably sodium carbonate, cesium carbonate or potassium carbonate.

This reaction can be carried out using a phase transfer catalyst to facilitate the reaction. The phase transfer catalyst suitable for facilitating the reaction includes, for example, but not limited to, quaternary ammonium salts substituted with a group such as a straight or branched alkyl group having 1 to about 18 carbon atoms, a phenyl lower alkyl group including a straight or branched alkyl group having 1 to 6 carbon atoms which is substituted by a phenyl group, and preferably tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium fluoride, tetrabutylammonium iodide, tetrabutylammonium hydroxide, tetrabutylammonium hydrogen sulfate, tributylmethylammonium chloride, tributylbenzylammonium chloride, tetraethylammonium chloride, tetramethylammonium chloride, tetrapentylammonium chloride, tetrapentylammonium bromide, tetrahexyl ammonium chloride, benzyldimethyloctylammonium chloride, methyltrihexylammonium chloride, benzylmethyloctadecanylammonium chloride, methyltridecanylammonium chloride, benzyltripropylammonium chloride, benzyltriethyl ammonium chloride, phenyltriethylammonium chloride and the like; phosphonium salts substituted with a residue such as a straight or branched alkyl group having 1 to about 18 carbon atoms, and preferably tetrabutylphosphonium chloride and the like; and pyridinium salts substituted with a straight or branched alkyl group having 1 to about 18 carbon atoms, and preferably 1-dodecanylpyridinium chloride and the like.

More preferably the phase transfer catalyst is tetrabutylammonium bromide, tetrabutylphosphonium bromide, tetrabutylammonium chloride, tetrabutylphosphonium chloride, benzyltriethylammonium chloride or tetrabutylammonium hydrogen sulfate, and further more preferably tetrabutylammonium bromide.

The reaction of this step is carried out at a temperature of about 30°C to about 120°C, preferably at a temperature of about 40°C to about 90°C, and more preferably at a temperature of about 50°C to about 60°C. The reaction time may vary from about 10 hours to about 40 hours, preferably about 10 hours to about 30 hours, and more preferably about 15 hours to about 20 hours.

The reaction mass containing the compound of formula VII obtained in this step may be subjected to usual work up such as a washing, an extraction, a pH adjustment, evaporation, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula I, or the compound of formula VII may be isolated as crystalline solid and then used in the next step.

The compound of formula VII is isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.

The solvent used to isolate the compound of formula VII may be an aliphatic ether, a hydrocarbon solvent and a mixture thereof. Preferably, the solvent is n-heptane, n-pentane, n-hexane, cyclohexane, methyl tert-butyl ether, diisopropyl ether and a mixture thereof. The most preferable solvent is a mixture of methyl tert-butyl ether and n-heptane.

5. The fifth step is a deprotection of the compound of formula VII by hydrolysis or hydrogenation and, if necessary, an acid addition salt formation.

The solvent used in this step includes, but are not limited to, an alcohol, a hydrocarbon, a cyclic ether, an aliphatic ether, a chlorinated hydrocarbon and a mixture thereof. Preferably the solvent is methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, dichloromethane, dichloromethane, chloroform and a mixture thereof; and more preferably 2-methyltetrahydrofuran, methanol, ethanol, isopropyl alcohol, tetrahydrofuran and a mixture thereof.

The acid used in this step includes, for example, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, p-toluene sulfonic acid, trifluoroacetic acid or a mixture thereof.

The base used in this step includes, for example, and not limited to, methylamine, ethylamine, hydrazine, and ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide, and preferably aqueous sodium hydroxide, lithium hydroxide and potassium hydroxide.

The hydrogenating agent used in this step includes, but are not limited to, noble metal catalysts such as palladium, ruthenium, rhodium, platinum and their derivatives in the presence of hydrogen; Raney-nickel in the presence or the absence of hydrogen and a mixture thereof.

The acid hydrolysis or hydrogenation reaction in this step may be carried out at a temperature of about 0°C to about 100°C, preferably at a temperature of about 15°C to about 80°C, and more preferably at a temperature of about 30°C to about 50°C. The reaction time may vary from about 1 hour to about 35 hours, preferably about 5 hours to about 30 hours, and more preferably about 15 hours to about 25 hours.

The reaction mass containing the (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or a stereochemically isomeric form or a mixture of stereochemically isomeric forms or acid addition salts thereof obtained in this step may be subjected to usual work up such as a filtering off the insoluble matters, a washing, an extraction, a pH adjustment, direct evaporation or a combination thereof. (S)-(Tetrahydrofuran-3-yl)hydrazine of formula I or a stereochemically isomeric form or a mixture of stereochemically isomeric forms or acid addition salts thereof may be isolated from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof. The solvent for isolation may be an alcohol, a ketone, an ester, an aliphatic ether, a hydrocarbon solvent, a chlorinated hydrocarbon and a mixture thereof. Preferably, the solvent is methanol, ethanol, acetone, isopropanol, ethyl acetate, butyl acetate, methyl tert-butyl ether, toluene, n-heptane, n-pentane, n-hexane, cyclohexane and a mixture thereof.

(S)-(Tetrahydrofuran-3-yl)hydrazine of formula I or a stereochemically isomeric form or a mixture of stereochemically isomeric forms thereof obtained by hydrogenation process may be converted to an acid addition salt using suitable acid in high purity.

The acid addition salt of the (S)-(tetrahydrofuran-3-yl)hydrazine of formula I is prepared by the reaction of the compound of formula I with a suitable acid in a suitable solvent, followed by isolating and/or recovering the substantially pure acid addition salt of the (S)-(tetrahydrofuran-3-yl)hydrazine of formula I.

The acid addition salt of the compound of formula I is provided in a solid state form, a crystalline form or an amorphous form.

The solvent used for preparing the acid addition salt of the compound of formula I may be methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, methylene chloride, ethylene dichloride, chloroform, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide and a mixture thereof.

The acid to form an acid addition salt of the compound of formula I is, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, glutaric acid, citraconic acid, glutaconic acid, tartaric acid, mandelic acid, dibenzoyl-L-tartaric acid, di-p-toluoyl-L-tartaric acid, di-p-anisoyl-L-tartaric acid, (R)-(-)-α-methoxyphenylacetic acid, L-malic acid, (lS)-(+)-10-camphorsulfonic acid, (R) or (S)-α-methoxy-α-(trifluoromethyl)phenylacetic acid (Mosher's acid), (S)-(-)-(2-phenylcarbamoyloxy)propionic acid [(S)-(-)-carbamalactic acid], (R) or (S)-para-methylmandelic acid, (R) or (S)-ortho-chloromandelic acid, (R) or (S)-2-hydroxymethylhexanoic acid, (R) or (S)-2-hydroxymethylbutanoic acid, and (R) or (S)-2-hydroxymethylpropanoic acid.

Preferable acid addition salts of the compounds of formula I are hydrochloride salt, hydrobromide salt, L-tartrate salt, dibenzoyl-L-tartrate salt, di-p-toluoyl-L-tartrate salt, di-p-anisoyl-L-tartrate salt, (R)-(-)-mandelate salt, (R)-(-)-α-methoxyphenylacetate salt, L-malate salt, (lS)-(+)-10-camphorsulfonate salt, (R) or (S)-α-methoxy-α-(trifluoromethyl)phenylacetate salt, (S)-(-)-(2-phenylcarbamoyloxy)propionate salt, (R) or (S)-para-methylmandelate salt, (R) or (S)-ortho-chloromandelate salt, (R) or (S)-2-hydroxymethylhexanoate salt, (R) or (S)-2-hydroxymethylbutanoate salt or (R) or (S)-2-hydroxymethylpropanoate salt.

The term "substantially pure (S)-(tetrahydrofuran-3-yl)hydrazine of formula I" refers to the (S)-(tetrahydrofuran-3-yl)hydrazine of formula I having a total purity, including both stereochemical and chemical purity, of greater than about 95%, preferably greater than about 98%, more preferably greater than about 99%, and still more preferably greater than about 99.5%. The purity is preferably measured by High Performance Liquid Chromatography (HPLC). For example, the purity of the (S)-(tetrahydrofuran-3-yl)hydrazine of formula I obtained by the process disclosed herein is about 95% to about 99%, or about 98% to about 99.5%, as measured by HPLC.

Following analytical methods are applied for evaluation of target compounds.

A) Reaction monitoring and HPLC purity by RI Detector for Example-04 product
Chromatographic conditions:
Column: Inertsil ODS-3V (150mm x 4.6mm), 5&micro;m
Column temperature: 30°C
Sample temperature: 10°C
Mobile phase: 0.01M NH₄OAc in Water: Acetonitrile (50:50%V/V)
Flow rate: 1.0mL/min
Injection volume: 20&micro;L
Run time: 45min
Diluent: Mobile phase
Needle wash: Acetonitrile: Water (50:50%v/v)
RI Sensitivity: 64
Internal Temp: 30°C
Sampling Rate: 2
Sample concentration: 4.0mg/mL

B) HPLC purity by RI Detector for Example-05 and Example-06 products
Chromatographic conditions:
Column: Restek ultra Aq C18 (150mm x 4.6mm), 5&micro;m
Column temperature: 30°C
Sample temperature: 10°C
Mobile phase: 0.02M NH₄OAc in Water: Methanol (87:13%V/V)
Flow rate: 0.4mL/min (Initial flow)
Injection volume: 20&micro;L
Run time: 55min
Diluent: Mobile phase
Needle wash: Methanol: Water (13:87%V/V)
RI Sensitivity: 512
Internal Temp: 35°C
Sample concentration: 2.0mg/mL
Flow Gradient Program:

C) Chiral purity HPLC method by RI Detector for Example-05 and Example-06 products
Chromatographic conditions:
Column: CHIRALPAK AD-H (250mm x 4.6mm), 5&micro;m
Mobile Phase: n-Hexane: Ethanol: Diethylamine (500:500:1.0 v/v)
Flow Rate: 0.8 ml/min
Injection Volume: 50&micro;l
Column Temp: 35°C
Sample Temp: Ambient
Diluent: Mobile Phase
Run Time: 20min
Sample Concentration: 2 mg/ml
Sampling Rate: 2
RI Sensitivity: 256
Internal Temp: 35°C
Racemic solution Preparation:
Accurately weigh and transfer about 20 mg of racemic mix into 10 ml volumetric flask, add 5 ml diluent, sonicate to dissolve and make up to the mark with diluent.
Sample Solution Preparation:
Accurately weigh and transfer about 20 mg of Example-05 or Example-06 sample into 10 ml volumetric flask, add 5 ml diluent, sonicate to dissolve and make up to the mark with diluent.

D) Free Hydrazine Content by HPLC method in Example-05 and Example-06 products by RI detector
Chromatographic Conditions:
Column: YMC Pack ODS Aq (250mm x 4.6mm), 5&micro;m
Mobile phase: 0.1% Trifluoroacetic Acid in (Water: Methanol (95:5%V/V))
Elution: Isocratic (100% Mobile phase)
Flow Rate: 0.5ml/min
Injection Volume: 20&micro;l
Column Temperature: 30°C
Diluent: Mobile phase
Run Time: 20min
Detector: RI Detector
Sensitivity: 256
Internal Temp: 35°C
Sampling Rate: 2
Sample Concentration: 2mg/ml
Standard used: Hydrazine hydrate

E) GC Method conditions for Example-01 to Example-03:
Reagent/Solvents: Ethanol (HPLC grade or equivalent)
Chromatographic conditions:
Column: Rtx-5-Amine (15m x 0.53mm x 3.0&micro;m)
Oven temperature program: from 50°C up to 140°C by 5°C/min and up to 240°C by 20°C/min (hold for 12 min)
Carrier gas (Helium): 4.0 mL/min
Split ratio: 50:1
Injector temperature: 220°C
Detector temperature: 250°C
Hydrogen flow: 30 mL/min
Zero-Air flow: 300 mL/min
Make-up flow (Helium): 25 mL/min
Injection volume: 1.0 &micro;L
Run time: 35.0 min
Diluent: Ethanol
Syringe rinsing solution: Ethanol
Syringe pre-rinsing: 4 pumps
Syringe post-rinsing: 4 pumps
Syringe rinses with sample: 4 pumps
Detection: Flame ionization
Retention time:
(R)-ethyl 4-chloro-3-hydroxybutyrate is about 16.1 min.
Example-01 compound is about 13.9 min
Example-02 compound is about 6.9 min
Exmaple-03 compound is about 25.2 min
Preparation of sample solution:
Accurately transfer about 1.0 mL of test sample into 10 mL volumetric flask. Dissolve and dilute up to the mark with diluent. Prepare sample in duplicate.
Procedure:
Follow the below sequence of injections for sample analysis

Aptly the process for the preparation of the (S)-(tetrahydrofuran-3-yl)hydrazine of formula I described herein is adapted to the preparation of 1H-pyrazolo[4,3-c]quinolin-4(5H)-one derivatives or their pharmaceutically acceptable acid addition salts, in high enantiomeric and chemical purity.

All ranges disclosed hereinafter are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the claims

Example-01 Preparation of (R)-4-chloro-1,3-butanediol

(R)-Ethyl 4-chloro-3-hydroxybutyrate (250.0 g) was charged into a cooled mixture of toluene (1000 ml) and sodium borohydride (51.09 g, 0.9 eq.) maintaining temperature between -5 to 5°C under nitrogen atmosphere followed by stirring at the same temperature for 30 minutes. Then methanol (43.30 g, 0.9 eq.) was added dropwise maintaining temperature between -5 to 5°C followed by stirring for 30 minutes at -5 to 5°C. The temperature of the reaction mass was increased to 10 to 15°C followed by stirring of the reaction mass for 1 hour at same temperature. Then reaction mass temperature was increased to 20-25°C followed by stirring at the same temperature till reaction completion. After completion of the reaction monitored by thin layer chromatography, cooled the reaction mass to 0 to 10°C followed by quenching by addition of conc. hydrochloric acid (156.48 g) followed by distillation of reaction mass under reduced pressure by maintaining temperature below 40°C. The traces of toluene was removed by co-distillation with methanol (3 x 270 ml) followed by addition of methyl tert-butyl ether (675 ml) to the concentrated mass. The resulting suspension was stirred for 30 minutes followed by filtration to remove inorganic materials. The solid cake was washed with methyl tert-butyl ether (100 ml) followed by distillation under reduced pressure maintaining temperature below 40°C to obtain (R)-4-chloro-1,3-butanediol as an oil (193.75 g, 103.64%).
Mass [M+H]: 124.79
Purity by GC-93.67% area
Specific optical rotation (C=1, Methanol): + 23.08°

Example-02 Preparation of (R)-tetrahydrofuran-3-ol

Dilute hydrochloric acid (17.5 ml of conc. hydrochloric acid diluted with 332.50 ml of water) was added to (R)-4-chloro-1,3-butanediol (175 g) and stirring was performed for 2 hours under reflux. After completion of the reaction monitored by gas chromatography, the reaction mixture was cooled to 0 to 5°C followed by a pH adjustment between 7 to 8 by using aqueous sodium hydroxide solution (82.5 g of sodium hydroxide dissolved in 165 ml of water). The resulting reaction mass was diluted with methanol (525 ml) followed by distillation under reduced pressure maintaining temperature below 45°C. Water was completely removed using methanol stripping (2 x 525 ml) followed by addition of methyl tert-butyl ether (525 ml) to the concentrated mass. The resulting suspension was stirred for 30 minutes followed by filtration to remove inorganic materials. The solid cake was washed with methyl tert-butyl ether (100 ml) followed by distillation under reduced pressure maintaining temperature below 40°C to obtain a crude oil (88.46 g). The resulting crude material was distilled under reduced pressure at 90 to 95°C (5 mmHg pressure) to give pure (R)-tetrahydrofuran-3-ol as an oil (73.62 g, 59.47 %).
¹H-NMR: (400 MHz, CDCl₃): δ: 4.44-4.45 (m, 1H), 3.90-3.97 (m, 1H), 3.69-3.80 (m, 2H), 3.02-3.12 (brs, 1H), 2.00-2.08 (m, 1H), 1.84-2.00 (m, 1H)
Mass [M+H]: 88.81
Purity by GC: 99.43% area
Specific optical Rotation (C= 1, Methanol): -17.57°

Example-03 Preparation of (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate

To a stirred solution of (R)-tetrahydrofuran-3-ol (65 g) and toluene (325 ml), were added N-methylmorpholine (111.93 g, 1.5 eq.) and 1-methylimidazole (30.28 g, 0.5 eq.) at 15 to 20°C followed by portion-wise addition of p-toluenesulfonyl chloride (187.0 g, 1.33 eq.) maintaining temperature between 0 to 10°C. The reaction mass temperature was increased to 15 to 25°C followed by stirring at same temperature till completion of reaction (generally 2 hrs are taken) monitored by gas chromatography. After completion of the reaction, the reaction mass was quenched by addition of water (325 ml), maintaining temperature from 15 to 25°C. The resulting layers were separated followed by back extraction of aqueous layer using toluene (195 ml). The combined toluene layer was washed by using dilute hydrochloric acid (16.25 ml conc. hydrochloric acid and 308.75 ml of water) followed by aqueous sodium bicarbonate solution (16.25 g sodium bicarbonate in 325 ml of water) followed by aqueous sodium chloride solution (32.5 g of sodium chloride in 325 ml of water). The toluene layer was concentrated under reduced pressure maintaining temperature below 40°C to give 179.18 g (100.24%) of (R)-tetrahydrofuran-3-yl 4-methylbenzenesulfonate as an oil.
¹H NMR (400 MHz, CDCl₃): δ: 7.75-7.77 (d, J= 8 Hz, 2H), 7.32-7.34 (d, J= 8 Hz, 2H), 5.06-5.09 (m, 1H), 3.82-3.88 (q, J= 8 Hz, 2H) 3.74-3.80 (m, 2H), 2.42 (s, 3H), 2.03-2.07 (m, 2H)
Mass [M+H]: 242.72
Purity by GC: 98.62% area
Specific Optical rotation (C=1, Methanol): + 4.354°

Example-04 Preparation of (S)-tri-tert-butyl 2-(tetrahydrofuran-3-yl)hydrazine-1,1,2-tricarboxylate

To a stirred solution of tri-tert-butyl hydrazine-1,1,2-tricarboxylate (58.5 g, 0.95 eq., prepared as per Angew. Chem. Int. Ed. 1996, 35, No. 22, 2626-2627) in dimethylsulfoxide (180 ml), was added cesium carbonate (90.77 g, 1.5 eq.), followed by stirring for 30 minutes at 20 to 30°C. (R)-Tetrahydrofuran-3-yl 4-methylbenzenesulfonate (45.0 g, 1.0 eq.) was added into the reaction mass, followed by increase of temperature to 50 to 55°C. The resulting reaction mass was stirred at 50 to 55°C till tri-tert-butyl hydrazine-1,1,2-tricarboxylate is less than 0.25% monitored by HPLC area %. After completion of the reaction, the reaction mass was cooled to 20 to 25°C, followed by addition of water (225 ml) and methyl tert-butyl ether (450 ml). The resulting biphasic mixture was stirred for 10 minutes followed by layer separation. The resulting organic layer was washed with an aqueous sodium chloride solution (225ml) followed by solvent evaporation under reduced pressure to give crude (S)-tri-tert-butyl 2-(tetrahydrofuran-3-yl)hydrazine-1,1,2-tricarboxylate (68.34 g). The crude material was recrystallized using a mixture of methyl tert-butyl ether and n-heptane (22.5 ml : 112.50 ml) to give pure (S)-tri-tert-butyl 2-(tetrahydrofuran-3-yl)hydrazine-1,1,2-tricarboxylate (57.96 g , 77.53%).
Mass [M+H]: 402.80
Purity by HPLC: 99.59% area
Specific Optical Rotation (C=1, Methanol): -8.553°
Melting point (DSC method): 62.71°C

Example-05 Preparation of (S)-(tetrahydrofuran-3-yl)hydrazine hydrochloride

To a cooled solution of (S)-tri-tert-butyl 2-(tetrahydrofuran-3-yl)hydrazine-1,1,2-tricarboxylate (50.0 g) and methanol (350 ml), was added conc. hydrochloric acid (110 ml) maintaining temperature between 0-10°C, followed by stirring for 30 minutes at the same temperature. The resulting mass temperature was increased to 20-25°C, followed stirring till completion of reaction (~20 hrs) as monitored by thin layer chromatography. After completion of the reaction, resulting reaction mass was distilled under reduced pressure maintaining temperature below 40°C followed by strip out using methanol (2 x 50 ml) and isopropyl alcohol (100 ml). Isopropyl alcohol (150 ml) was added into the concentrated mass followed by stirring for 1 hr at 20-25°C. Then suspension was cooled further to -15 to -5°C followed by stirring for 1 hr at the same temperature. The resulting suspension was filtered followed by washing of wet material with chilled isopropyl alcohol (50 ml). The wet material was dried under reduced pressure maintaining temperature below 40°C to obtain (S)-(tetrahydrofuran-3-yl) hydrazine hydrochloride as a pure off white solid (16.5 g, 95.81%).
¹H NMR (400 MHz, DMSO, D-Exchange): δ: 8.73 (brs, 3H), 3.70-3.80 (m, 3H), 3.59-3.67 (m, 2H), 1.98-2.07 (m, 1H), 1.84- 1.91 (m, 1H)
Mass [M+H]: 102.92
Purity by HPLC: 99.69% area
Chiral Purity by HPLC: 99.91%
Hydrazine content by HPLC: 0.30% w/w
Chloride content: 25.27% w/w
Moisture content: 0.32% w/w
Specific optical rotation (C= 1, Methanol): -12.678°

Example-06 Preparation of (S)-(tetrahydrofuran-3-yl)hydrazine hydrochloride (alternative of Example-05)

To a cooled conc. hydrochloric acid (600 ml) was added (S)-tri-tert-butyl 2-(tetrahydrofuran-3-yl)hydrazine-1,1,2-tricarboxylate (200.0 g) maintaining temperature below 10°C. The resulting mass temperature was increased to 20-25°C, followed stirring till completion of reaction (3 hrs) as monitored by thin layer chromatography. After completion of the reaction, toluene (400ml) was added to reaction mass followed by distillation under reduced pressure maintaining temperature below 40°C followed by strip out using toluene (400 ml) and isopropyl alcohol (2 x 200 ml). Isopropyl alcohol (300 ml) was added into the concentrated mass followed by stirring for 1 hr at 20-25°C. Then suspension was cooled further to 20 to -15°C followed by stirring for 1 hr at the same temperature. The resulting suspension was filtered followed by washing of wet material with chilled isopropyl alcohol (50 ml). The wet material was dried under reduced pressure maintaining temperature below 40°C to obtain (S)-(tetrahydrofuran-3-yl)hydrazine hydrochloride as a pure off white solid (63.50 g, 92.19%).
¹H NMR (400 MHz, DMSO, D-Exchange): δ: 3.74-3.80 (m, 3H), 3.59-3.69 (m, 2H), 2.02-2.07 (m, 1H), 1.84- 1.87 (m, 1H)
Mass [M+H]: 102.90
Purity by HPLC: 99.94% area
Chiral Purity by HPLC: 99.98%
Hydrazine content by HPLC: 0.03% w/w
Chloride content: 25.65% w/w
Moisture content: 0.23% w/w
Specific optical rotation (C= 1, Methanol): -12.953°

Claims (12)

1. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof, comprising (e) hydrolysis or hydrogenation step of protected hydrazine compound of formula VII,
   

   

   wherein R^a is a tert-butyl group or a benzyl group.
2. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 1, comprising (d) reacting step of the compound of formula V with the compound of formula VI to produce the protected hydrazine compound of formula VII, and (e) hydrolysis or hydrogenation step of the protected hydrazine compound of formula VII,
   

   

   wherein R^a is the same definition as in claim 1, OE is an ester residue of sulfonic acid, phosphonic acid and phosphoric acid selected from the group consisting of
   

   

   wherein R^b is i) a C1-6 alkyl group optionally substituted with one to five halogen atoms, or ii) a C6-14 aryl group optionally substituted with one to three substituents selected from the group consisting of a C1-6 alkyl group, a halogen atom and a nitro group.
3. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 2, comprising (c) reacting step of the compound of formula IV with an esterifying reagent to produce the compound of formula V, (d) reacting step of the compound of formula V with the compound of formula VI to produce the protected hydrazine compound of formula VII, and (e) hydrolysis or hydrogenation step of the protected hydrazine compound of formula VII,
   

   

   wherein R^a and OE are the same definitions as in claim 2.
4. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 3, comprising (b) reacting step of the compound of formula III in acidic or basic conditions to produce the compound of formula IV, (c) reacting step of the compound of formula IV with an esterifying reagent to produce the compound of formula V, (d) reacting step of the compound of formula V with the compound of formula VI to produce the protected hydrazine compound of formula VII, and (e) hydrolysis or hydrogenation step of the protected hydrazine compound of formula VII,
   

   

   wherein R^a and OE are the same definitions as in claim 3, and X is a halogen atom.
5. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 4, comprising (a) reduction step of the compound of formula II to produce the compound of formula III, (b) reacting step of the compound of formula III in acidic or basic conditions to produce the compound of formula IV, (c) reacting step of the compound of formula IV with an esterifying reagent to produce the compound of formula V, (d) reacting step of the compound of formula V with the compound of formula VI to produce the protected hydrazine compound of formula VII, and (e) hydrolysis or hydrogenation step of the protected hydrazine compound of formula VII,
   

   

   wherein R^a, OE and X are the same definitions as in claim 4, R^c is a C1-6 alkyl group, a C6-14 aryl group or a C3-8 cycloalkyl group.
6. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 1, wherein R^a is a tert-butyl group.
7. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 2, wherein R^a is a tert-butyl group, and OE is a 4-methylbenzenesulfonyloxy group.
8. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 3, wherein R^a is a tert-butyl group, and OE is a 4-methylbenzenesulfonyloxy group.
9. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 4, wherein R^a is a tert-butyl group, OE is a 4-methylbenzenesulfonyloxy group, and X is a chlorine atom.
10. A process for production of (S)-(tetrahydrofuran-3-yl)hydrazine of formula I or an acid addition salt thereof as claimed in claim 5, wherein R^a is a tert-butyl group, OE is a 4-methylbenzenesulfonyloxy group, X is a chlorine atom, and R^c is an ethyl group.
11. A compound of formula VII
    

    

    wherein R^a is a tert-butyl group or a benzyl group.
12. A compound of formula VII as claimed in claim 11, wherein R^a is a tert-butyl group.